Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0007219 Notch signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex. Reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x). Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007411 axon guidance	IBA GO_REF:0000033	REMOVE	Summary: The PANTHER IBA axon-guidance annotation appears to come from the broad PTHR45836 family, which includes both Notch receptors and canonical SLIT axon-guidance ligands. Reason: Notch1 is a Notch receptor subfamily member, whereas axon guidance is a primary SLIT-family function in the same broad PANTHER family. The PANTHER metadata and reviewed member table support treating this as a family-transfer artifact rather than a Notch1 core function. Supporting Evidence: file:interpro/panther/PTHR45836/PTHR45836-metadata.yaml PTHR45836 is named Notch and Slit guidance protein and includes both Notch signaling and axonal guidance descriptions. file:interpro/panther/PTHR45836/PTHR45836-entries.csv Reviewed members include mouse Notch1 in subfamily SF12 and mouse/human Slit proteins in separate SLIT subfamilies. file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0009986 cell surface	IBA GO_REF:0000033	ACCEPT	Summary: Notch1 is expressed at the cell surface where it functions as a receptor for trans-acting ligands on neighboring cells. Reason: Cell surface localization is essential for Notch1 receptor function. The extracellular domain (N(EC)) binds ligands at the cell surface, triggering the proteolytic cascade. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0043235 receptor complex	IBA GO_REF:0000033	ACCEPT	Summary: Notch1 exists as a heterodimeric receptor complex formed by furin cleavage during maturation. The N(EC) and N(TM) fragments remain associated at the cell surface. Reason: Notch1 forms a heterodimeric complex after S1 furin cleavage in the Golgi. The extracellular and transmembrane fragments are non-covalently associated. This is well-documented in UniProt and structural studies. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0001525 angiogenesis	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 plays a key role in angiogenesis by negatively regulating endothelial cell proliferation and migration. DLL4-Notch1 signaling controls tip/stalk cell selection during vascular development. Reason: While angiogenesis is a well-documented biological context for Notch1 function, it represents a tissue-specific outcome rather than the core molecular function. UniProt confirms Notch1 is involved in angiogenesis, negatively regulating endothelial cell proliferation. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0001701 in utero embryonic development	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in in utero embryonic development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0001947 heart looping	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 is required for proper cardiac morphogenesis including heart looping during development. Reason: Heart looping is a specific developmental process. Notch1 mutations cause congenital heart defects (AOVD1), confirming cardiac development roles, but this is tissue-specific. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0002011 morphogenesis of an epithelial sheet	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in morphogenesis of an epithelial sheet, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0002064 epithelial cell development	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in epithelial cell development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0002437 inflammatory response to antigenic stimulus	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in inflammatory response to antigenic stimulus, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005509 calcium ion binding	IEA GO_REF:0000002	ACCEPT	Summary: Notch1 contains multiple EGF-like domains that bind calcium ions, which are essential for proper domain folding and ligand binding. Reason: Calcium binding is a core molecular function of Notch1. The EGF-like calcium-binding domains (IPR001881) are essential for Notch1 structure and function. UniProt lists calcium ion binding in the domain annotations. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription. Reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005829 cytosol	IEA GO_REF:0000117	ACCEPT	Summary: Cytosol Reason: NICD released to cytosol before nuclear import. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0006355 regulation of DNA-templated transcription	IEA GO_REF:0000002	MODIFY	Summary: NICD forms a transcriptional activation complex with RBPJ and MAML to regulate target gene expression. Reason: The broad transcription-regulation parent is correct but too general for Notch1. The supported biology is NICD/RBPJ/MAML-dependent positive regulation of canonical Notch target transcription. Proposed replacements: positive regulation of transcription of Notch receptor target positive regulation of DNA-templated transcription Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0006959 humoral immune response	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in humoral immune response, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007219 Notch signaling pathway	IEA GO_REF:0000120	ACCEPT	Summary: Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex. Reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x). Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010001 glial cell differentiation	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in glial cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010718 positive regulation of epithelial to mesenchymal transition	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 promotes positive regulation of epithelial to mesenchymal transition. Reason: EMT regulation - context-dependent function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010720 positive regulation of cell development	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in positive regulation of cell development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0012505 endomembrane system	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in endomembrane system, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0016020 membrane	IEA GO_REF:0000120	MODIFY	Summary: Notch1 is a type I transmembrane protein that localizes to various cellular membranes during its lifecycle. Reason: Generic membrane is true but too broad for curation. Notch1 localization is better represented by the specific plasma membrane, Golgi membrane, endoplasmic reticulum membrane, and late endosome membrane annotations already present in this review. Proposed replacements: plasma membrane Golgi membrane endoplasmic reticulum membrane late endosome membrane Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030154 cell differentiation	IEA GO_REF:0000002	ACCEPT	Summary: Notch1 is a master regulator of cell-fate determination and differentiation across multiple tissue contexts. Reason: Cell differentiation regulation is a core biological role of Notch1 signaling. UniProt states Notch1 affects implementation of differentiation, proliferation and apoptotic programs. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030326 embryonic limb morphogenesis	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in embryonic limb morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030513 positive regulation of BMP signaling pathway	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of bmp signaling pathway. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030858 positive regulation of epithelial cell differentiation	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in positive regulation of epithelial cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0031902 late endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: Non-activated Notch1 receptor is targeted for lysosomal degradation via the endosomal pathway. Reason: UniProt explicitly states late endosome membrane localization and notes that non-activated receptor is targeted for lysosomal degradation via the endosomal pathway. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0035850 epithelial cell differentiation involved in kidney development	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in epithelial cell differentiation involved in kidney development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0038023 signaling receptor activity	IEA GO_REF:0000002	MODIFY	Summary: Notch1 functions as a signaling receptor that transduces cell-cell contact signals into transcriptional responses. Reason: Signaling receptor activity is correct but too generic for Notch1, which is specifically a transmembrane receptor activated by membrane-bound ligands and regulated proteolysis. Proposed replacements: transmembrane signaling receptor activity Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0042981 regulation of apoptotic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in regulation of apoptotic process, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045165 cell fate commitment	IEA GO_REF:0000117	ACCEPT	Summary: cell fate commitment is consistent with canonical mouse Notch1 receptor biology. Reason: Falcon synthesis identifies the conserved Notch1 mechanism as ER/Golgi maturation, plasma-membrane ligand reception, regulated proteolysis, NICD nuclear entry, and CSL/RBPJ-MAML transcriptional activation. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0048589 developmental growth	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in developmental growth, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0048608 reproductive structure development	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in reproductive structure development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0048844 artery morphogenesis	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in artery morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0050793 regulation of developmental process	IEA GO_REF:0000002	ACCEPT	Summary: Notch1 is a key regulator of developmental processes including cell fate determination. Reason: Developmental regulation is a well-established function of Notch1. UniProt notes roles in postimplantation development, mesoderm development, somite formation, and neurogenesis. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0070986 left/right axis specification	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 annotation to left/right axis specification. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0072012 glomerulus vasculature development	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in glomerulus vasculature development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0072080 nephron tubule development	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in nephron tubule development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:2000136 regulation of cell proliferation involved in heart morphogenesis	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in regulation of cell proliferation involved in heart morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:17210915 Baf60c is a nuclear Notch signaling component required for t...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:21102556 RITA, a novel modulator of Notch signalling, acts via nuclea...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:22258620 Pten coordinates retinal neurogenesis by regulating Notch si...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:38891776 Pin1 Downregulation Is Involved in Excess Retinoic Acid-Indu...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:8749394 Physical interaction between a novel domain of the receptor ...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0000122 negative regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 can negatively regulate certain genes through target gene specificity and crosstalk with repressive mechanisms. Reason: While Notch1 primarily activates transcription, it can also lead to repression of certain targets depending on context. This is a secondary regulatory outcome. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0001554 luteolysis	IEA GO_REF:0000107	UNDECIDED	Summary: The imported luteolysis annotation lacks gene-specific positive support in the local evidence for mouse Notch1. Reason: Luteolysis is a specialized reproductive process and the available Falcon/UniProt context does not substantiate a specific Notch1 role beyond the imported electronic annotation. Leave undecided pending direct reproductive-context evidence.
GO:0001669 acrosomal vesicle	IEA GO_REF:0000107	REMOVE	Summary: The imported acrosomal vesicle annotation lacks direct mouse Notch1 localization support in the local evidence. Reason: Notch1 has well-supported membrane, endosomal, and nuclear NICD localizations, but no local evidence links mouse Notch1 to acrosomal vesicle localization or sperm acrosome biology. The imported automated localization should be removed rather than retained as undecided.
GO:0001837 epithelial to mesenchymal transition	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 promotes epithelial to mesenchymal transition. Reason: EMT regulation - context-dependent function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0002052 positive regulation of neuroblast proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 promotes neural progenitor/stem cell proliferation and maintains the undifferentiated state. Reason: Notch1 maintains neural stem cells and regulates neurogenesis, but this is a tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0002193 MAML1-RBP-Jkappa- ICN1 complex	IEA GO_REF:0000107	ACCEPT	Summary: MAML1-RBP-Jkappa-ICN1 complex Reason: Core transcription activation complex. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003151 outflow tract morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 annotation to outflow tract morphogenesis. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003180 aortic valve morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 is essential for aortic valve development. Notch1 mutations cause aortic valve disease (AOVD1). Reason: Strongly supported by mouse genetics - Notch1 mutations cause bicuspid aortic valve and calcific aortic valve disease (OMIM:109730). This is a key developmental phenotype but tissue-specific. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003184 pulmonary valve morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 regulates pulmonary valve development. Mouse Notch1 mutations cause pulmonary valve abnormalities. Reason: Cardiac valve development - tissue-specific developmental function supported by mouse genetics. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003192 mitral valve formation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 regulates mitral valve formation. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003264 regulation of cardioblast proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 regulates cardioblast proliferation during heart development. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003713 transcription coactivator activity	IEA GO_REF:0000107	ACCEPT	Summary: NICD functions as a transcriptional coactivator by converting RBPJ from a repressor to an activator. Reason: Transcription coactivator activity is a core molecular function of NICD. It recruits MAML and displaces corepressors from RBPJ. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0004888 transmembrane signaling receptor activity	IEA GO_REF:0000120	ACCEPT	Summary: Notch1 is a transmembrane receptor that transduces signals from cell-cell contact to transcriptional responses. Reason: This is the core molecular function of Notch1. It is a type I transmembrane receptor that signals via proteolytic processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007221 positive regulation of transcription of Notch receptor target	IEA GO_REF:0000120	ACCEPT	Summary: Positive regulation of transcription of Notch receptor target Reason: Core downstream function of NICD. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007283 spermatogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 annotation to spermatogenesis. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007507 heart development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 regulates heart development. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0008284 positive regulation of cell population proliferation	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of cell population proliferation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0008285 negative regulation of cell population proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of cell population proliferation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010628 positive regulation of gene expression	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of gene expression. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010629 negative regulation of gene expression	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of gene expression. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010667 negative regulation of cardiac muscle cell apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 regulates negative regulation of cardiac muscle cell apoptotic process. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010812 negative regulation of cell-substrate adhesion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of cell-substrate adhesion. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0021515 cell differentiation in spinal cord	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 is involved in cell differentiation in spinal cord. Reason: Neural development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0031100 animal organ regeneration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 annotation to animal organ regeneration. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0032496 response to lipopolysaccharide	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 is involved in response to lipopolysaccharide. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0032966 negative regulation of collagen biosynthetic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of collagen biosynthetic process. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0035148 tube formation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 annotation to tube formation. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0035924 cellular response to vascular endothelial growth factor stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 regulates cellular response to vascular endothelial growth factor stimulus. Reason: Vascular development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0042127 regulation of cell population proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 annotation to regulation of cell population proliferation. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0042246 tissue regeneration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 annotation to tissue regeneration. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0042802 identical protein binding	IEA GO_REF:0000107	ACCEPT	Summary: Notch1 can form homodimers through its heterodimerization domain. Mutations in this domain cause T-ALL. Reason: Notch1 homodimerization is documented and has functional significance. The study shows leukemia-associated mutations fall into distinct mechanistic classes affecting the HD domain. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0043235 receptor complex	IEA GO_REF:0000107	ACCEPT	Summary: Notch1 exists as a heterodimeric receptor complex formed by furin cleavage during maturation. The N(EC) and N(TM) fragments remain associated at the cell surface. Reason: Notch1 forms a heterodimeric complex after S1 furin cleavage in the Golgi. The extracellular and transmembrane fragments are non-covalently associated. This is well-documented in UniProt and structural studies. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045603 positive regulation of endothelial cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 regulates positive regulation of endothelial cell differentiation. Reason: Vascular development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045662 negative regulation of myoblast differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of myoblast differentiation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045665 negative regulation of neuron differentiation	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of neuron differentiation via Notch-mediated lateral inhibition, a canonical function in the neuron-glia binary fate decision. Reason: Notch1-mediated effects on neuron differentiation are well-supported developmental outputs, but they are tissue-context consequences of the core juxtacrine receptor/NICD transcription mechanism rather than the core function itself. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045687 positive regulation of glial cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 promotes glial cell differentiation via lateral inhibition, instructing multipotent progenitors toward glial fate. Reason: Glial differentiation is a supported neural-developmental output of Notch1 signaling, but it is a context-specific consequence rather than the core receptor/NICD transcription mechanism. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045893 positive regulation of DNA-templated transcription	IEA GO_REF:0000107	ACCEPT	Summary: NICD positively regulates transcription by forming a coactivator complex with RBPJ and MAML that displaces corepressors. Reason: Notch1 NICD functions as a transcriptional activator. The NICD-RBPJ-MAML complex recruits coactivators like p300 to activate target gene transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0046579 positive regulation of Ras protein signal transduction	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 has been reported to crosstalk with Ras/MAPK signaling in certain cellular contexts. Reason: This represents crosstalk with other signaling pathways rather than the core Notch1 function. The canonical Notch pathway does not involve direct Ras activation, though downstream effects can influence Ras signaling. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0048708 astrocyte differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 promotes astrocyte differentiation as part of gliogenesis, with Sox9 acting as critical downstream mediator. Reason: Astrocyte differentiation is a supported downstream neural-lineage outcome, but it is not the general core molecular or cellular function of Notch1. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0048709 oligodendrocyte differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 regulates oligodendrocyte differentiation (inhibitory role - promotes astrocyte over oligodendrocyte fate). Reason: Oligodendrocyte differentiation is a neural-lineage output of Notch1 signaling and should be retained as non-core rather than as the defining receptor/NICD function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0051152 positive regulation of smooth muscle cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 promotes vascular smooth muscle cell differentiation and is required for arterial smooth muscle development. Reason: Smooth muscle differentiation is a tissue-specific developmental outcome of Notch1 signaling rather than a core function. It represents one of many differentiation contexts where Notch1 plays a role. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060354 negative regulation of cell adhesion molecule production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of cell adhesion molecule production. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060412 ventricular septum morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 annotation to ventricular septum morphogenesis. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0062043 positive regulation of cardiac epithelial to mesenchymal transition	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 regulates positive regulation of cardiac epithelial to mesenchymal transition. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0070374 positive regulation of ERK1 and ERK2 cascade	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 can promote ERK1/2 signaling in certain cellular contexts, representing pathway crosstalk. Reason: ERK cascade regulation is not part of canonical Notch signaling but may occur through indirect mechanisms or crosstalk in specific contexts. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0071228 cellular response to tumor cell	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 has been implicated in tumor microenvironment responses. Reason: This is a specialized context-dependent role of Notch1 in cancer biology rather than a core function of the protein. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0071372 cellular response to follicle-stimulating hormone stimulus	IEA GO_REF:0000107	UNDECIDED	Summary: The imported cellular response to follicle-stimulating hormone stimulus annotation lacks gene-specific positive support in the local evidence for mouse Notch1. Reason: The available Falcon/UniProt context does not substantiate a specific Notch1 response to FSH. Leave undecided pending direct reproductive-endocrine evidence.
GO:0090051 negative regulation of cell migration involved in sprouting angiogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 regulates negative regulation of cell migration involved in sprouting angiogenesis. Reason: Vascular development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0097150 neuronal stem cell population maintenance	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 is involved in neuronal stem cell population maintenance. Reason: Neural development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:2000048 negative regulation of cell-cell adhesion mediated by cadherin	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of cell-cell adhesion mediated by cadherin. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:2000737 negative regulation of stem cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of stem cell differentiation. Reason: Stem cell regulation - context-dependent function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:2000811 negative regulation of anoikis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of anoikis. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:2001027 negative regulation of endothelial cell chemotaxis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Notch1 regulates negative regulation of endothelial cell chemotaxis. Reason: Vascular development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0000122 negative regulation of transcription by RNA polymerase II	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 can negatively regulate certain genes through target gene specificity and crosstalk with repressive mechanisms. Reason: While Notch1 primarily activates transcription, it can also lead to repression of certain targets depending on context. This is a secondary regulatory outcome. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0001837 epithelial to mesenchymal transition	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 promotes epithelial to mesenchymal transition. Reason: EMT regulation - context-dependent function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0002193 MAML1-RBP-Jkappa- ICN1 complex	ISO GO_REF:0000119	ACCEPT	Summary: MAML1-RBP-Jkappa-ICN1 complex Reason: Core transcription activation complex. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003151 outflow tract morphogenesis	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 annotation to outflow tract morphogenesis. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003180 aortic valve morphogenesis	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 is essential for aortic valve development. Notch1 mutations cause aortic valve disease (AOVD1). Reason: Strongly supported by mouse genetics - Notch1 mutations cause bicuspid aortic valve and calcific aortic valve disease (OMIM:109730). This is a key developmental phenotype but tissue-specific. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003184 pulmonary valve morphogenesis	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 regulates pulmonary valve development. Mouse Notch1 mutations cause pulmonary valve abnormalities. Reason: Cardiac valve development - tissue-specific developmental function supported by mouse genetics. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003192 mitral valve formation	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 regulates mitral valve formation. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003713 transcription coactivator activity	ISO GO_REF:0000119	ACCEPT	Summary: NICD functions as a transcriptional coactivator by converting RBPJ from a repressor to an activator. Reason: Transcription coactivator activity is a core molecular function of NICD. It recruits MAML and displaces corepressors from RBPJ. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0004888 transmembrane signaling receptor activity	ISO GO_REF:0000119	ACCEPT	Summary: Notch1 is a transmembrane receptor that transduces signals from cell-cell contact to transcriptional responses. Reason: This is the core molecular function of Notch1. It is a type I transmembrane receptor that signals via proteolytic processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005634 nucleus	ISO GO_REF:0000119	ACCEPT	Summary: The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription. Reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007219 Notch signaling pathway	ISO GO_REF:0000119	ACCEPT	Summary: Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex. Reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x). Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007507 heart development	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 regulates heart development. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0008284 positive regulation of cell population proliferation	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of cell population proliferation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0008285 negative regulation of cell population proliferation	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of cell population proliferation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010629 negative regulation of gene expression	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of gene expression. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010812 negative regulation of cell-substrate adhesion	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of cell-substrate adhesion. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0035148 tube formation	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 annotation to tube formation. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0035924 cellular response to vascular endothelial growth factor stimulus	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 regulates cellular response to vascular endothelial growth factor stimulus. Reason: Vascular development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0042802 identical protein binding	ISO GO_REF:0000119	ACCEPT	Summary: Notch1 can form homodimers through its heterodimerization domain. Mutations in this domain cause T-ALL. Reason: Notch1 homodimerization is documented and has functional significance. The study shows leukemia-associated mutations fall into distinct mechanistic classes affecting the HD domain. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045662 negative regulation of myoblast differentiation	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of myoblast differentiation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045893 positive regulation of DNA-templated transcription	ISO GO_REF:0000119	ACCEPT	Summary: NICD positively regulates transcription by forming a coactivator complex with RBPJ and MAML that displaces corepressors. Reason: Notch1 NICD functions as a transcriptional activator. The NICD-RBPJ-MAML complex recruits coactivators like p300 to activate target gene transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0046579 positive regulation of Ras protein signal transduction	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 has been reported to crosstalk with Ras/MAPK signaling in certain cellular contexts. Reason: This represents crosstalk with other signaling pathways rather than the core Notch1 function. The canonical Notch pathway does not involve direct Ras activation, though downstream effects can influence Ras signaling. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0051152 positive regulation of smooth muscle cell differentiation	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 promotes vascular smooth muscle cell differentiation and is required for arterial smooth muscle development. Reason: Smooth muscle differentiation is a tissue-specific developmental outcome of Notch1 signaling rather than a core function. It represents one of many differentiation contexts where Notch1 plays a role. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060354 negative regulation of cell adhesion molecule production	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of cell adhesion molecule production. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060412 ventricular septum morphogenesis	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 annotation to ventricular septum morphogenesis. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0070374 positive regulation of ERK1 and ERK2 cascade	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 can promote ERK1/2 signaling in certain cellular contexts, representing pathway crosstalk. Reason: ERK cascade regulation is not part of canonical Notch signaling but may occur through indirect mechanisms or crosstalk in specific contexts. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0071228 cellular response to tumor cell	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 has been implicated in tumor microenvironment responses. Reason: This is a specialized context-dependent role of Notch1 in cancer biology rather than a core function of the protein. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0071372 cellular response to follicle-stimulating hormone stimulus	ISO GO_REF:0000119	UNDECIDED	Summary: The imported cellular response to follicle-stimulating hormone stimulus annotation lacks gene-specific positive support in the local evidence for mouse Notch1. Reason: The available Falcon/UniProt context does not substantiate a specific Notch1 response to FSH. Leave undecided pending direct reproductive-endocrine evidence.
GO:0090051 negative regulation of cell migration involved in sprouting angiogenesis	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 regulates negative regulation of cell migration involved in sprouting angiogenesis. Reason: Vascular development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:2000048 negative regulation of cell-cell adhesion mediated by cadherin	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of cell-cell adhesion mediated by cadherin. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:2000737 negative regulation of stem cell differentiation	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of stem cell differentiation. Reason: Stem cell regulation - context-dependent function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:2000811 negative regulation of anoikis	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of anoikis. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:2001027 negative regulation of endothelial cell chemotaxis	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Notch1 regulates negative regulation of endothelial cell chemotaxis. Reason: Vascular development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0008285 negative regulation of cell population proliferation	IDA PMID:26491108 Notch-Tnf signalling is required for development and homeost...	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of cell population proliferation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0008285 negative regulation of cell population proliferation	IMP PMID:26491108 Notch-Tnf signalling is required for development and homeost...	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of cell population proliferation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:2000137 negative regulation of cell proliferation involved in heart morphogenesis	IDA PMID:26491108 Notch-Tnf signalling is required for development and homeost...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in negative regulation of cell proliferation involved in heart morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:2000137 negative regulation of cell proliferation involved in heart morphogenesis	IMP PMID:26491108 Notch-Tnf signalling is required for development and homeost...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in negative regulation of cell proliferation involved in heart morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:1990433 CSL-Notch-Mastermind transcription factor complex	ISO GO_REF:0000119	ACCEPT	Summary: CSL-Notch-Mastermind transcription factor complex is consistent with canonical mouse Notch1 receptor biology. Reason: Falcon synthesis identifies the conserved Notch1 mechanism as ER/Golgi maturation, plasma-membrane ligand reception, regulated proteolysis, NICD nuclear entry, and CSL/RBPJ-MAML transcriptional activation. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0001669 acrosomal vesicle	ISO GO_REF:0000096	REMOVE	Summary: The imported acrosomal vesicle annotation lacks direct mouse Notch1 localization support in the local evidence. Reason: Notch1 has well-supported membrane, endosomal, and nuclear NICD localizations, but no local evidence links mouse Notch1 to acrosomal vesicle localization or sperm acrosome biology. The orthology-imported localization should be removed rather than retained as undecided.
GO:0002052 positive regulation of neuroblast proliferation	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Notch1 promotes neural progenitor/stem cell proliferation and maintains the undifferentiated state. Reason: Notch1 maintains neural stem cells and regulates neurogenesis, but this is a tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003264 regulation of cardioblast proliferation	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Notch1 regulates cardioblast proliferation during heart development. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0004888 transmembrane signaling receptor activity	ISO GO_REF:0000096	ACCEPT	Summary: Notch1 is a transmembrane receptor that transduces signals from cell-cell contact to transcriptional responses. Reason: This is the core molecular function of Notch1. It is a type I transmembrane receptor that signals via proteolytic processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005634 nucleus	ISO GO_REF:0000096	ACCEPT	Summary: The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription. Reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	ISO GO_REF:0000096	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007219 Notch signaling pathway	ISO GO_REF:0000096	ACCEPT	Summary: Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex. Reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x). Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007221 positive regulation of transcription of Notch receptor target	ISO GO_REF:0000096	ACCEPT	Summary: Positive regulation of transcription of Notch receptor target Reason: Core downstream function of NICD. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007283 spermatogenesis	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Notch1 annotation to spermatogenesis. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010628 positive regulation of gene expression	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of gene expression. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010667 negative regulation of cardiac muscle cell apoptotic process	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Notch1 regulates negative regulation of cardiac muscle cell apoptotic process. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0032966 negative regulation of collagen biosynthetic process	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of collagen biosynthetic process. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0042127 regulation of cell population proliferation	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Notch1 annotation to regulation of cell population proliferation. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045603 positive regulation of endothelial cell differentiation	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Notch1 regulates positive regulation of endothelial cell differentiation. Reason: Vascular development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045665 negative regulation of neuron differentiation	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of neuron differentiation via Notch-mediated lateral inhibition, a canonical function in the neuron-glia binary fate decision. Reason: Notch1-mediated effects on neuron differentiation are well-supported developmental outputs, but they are tissue-context consequences of the core juxtacrine receptor/NICD transcription mechanism rather than the core function itself. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045687 positive regulation of glial cell differentiation	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Notch1 promotes glial cell differentiation via lateral inhibition, instructing multipotent progenitors toward glial fate. Reason: Glial differentiation is a supported neural-developmental output of Notch1 signaling, but it is a context-specific consequence rather than the core receptor/NICD transcription mechanism. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0048708 astrocyte differentiation	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Notch1 promotes astrocyte differentiation as part of gliogenesis, with Sox9 acting as critical downstream mediator. Reason: Astrocyte differentiation is a supported downstream neural-lineage outcome, but it is not the general core molecular or cellular function of Notch1. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0062043 positive regulation of cardiac epithelial to mesenchymal transition	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Notch1 regulates positive regulation of cardiac epithelial to mesenchymal transition. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0098685 Schaffer collateral - CA1 synapse	IMP PMID:21315255 Activity-induced Notch signaling in neurons requires Arc/Arg...	KEEP AS NON CORE	Summary: Notch1 annotation to Schaffer collateral - CA1 synapse. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0098685 Schaffer collateral - CA1 synapse	IDA PMID:21315255 Activity-induced Notch signaling in neurons requires Arc/Arg...	KEEP AS NON CORE	Summary: Notch1 annotation to Schaffer collateral - CA1 synapse. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0098685 Schaffer collateral - CA1 synapse	IMP PMID:26635527 Notch1 Regulates Hippocampal Plasticity Through Interaction ...	KEEP AS NON CORE	Summary: Notch1 annotation to Schaffer collateral - CA1 synapse. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0098685 Schaffer collateral - CA1 synapse	IDA PMID:26635527 Notch1 Regulates Hippocampal Plasticity Through Interaction ...	KEEP AS NON CORE	Summary: Notch1 annotation to Schaffer collateral - CA1 synapse. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0098839 postsynaptic density membrane	IEP PMID:21315255 Activity-induced Notch signaling in neurons requires Arc/Arg...	KEEP AS NON CORE	Summary: Notch1 annotation to postsynaptic density membrane. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0098839 postsynaptic density membrane	IDA PMID:21315255 Activity-induced Notch signaling in neurons requires Arc/Arg...	KEEP AS NON CORE	Summary: Notch1 annotation to postsynaptic density membrane. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0098839 postsynaptic density membrane	IDA PMID:26635527 Notch1 Regulates Hippocampal Plasticity Through Interaction ...	KEEP AS NON CORE	Summary: Notch1 annotation to postsynaptic density membrane. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0098978 glutamatergic synapse	IMP PMID:26635527 Notch1 Regulates Hippocampal Plasticity Through Interaction ...	KEEP AS NON CORE	Summary: Notch1 annotation to glutamatergic synapse. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0098978 glutamatergic synapse	IDA PMID:26635527 Notch1 Regulates Hippocampal Plasticity Through Interaction ...	KEEP AS NON CORE	Summary: Notch1 annotation to glutamatergic synapse. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0099565 chemical synaptic transmission, postsynaptic	IMP PMID:21315255 Activity-induced Notch signaling in neurons requires Arc/Arg...	KEEP AS NON CORE	Summary: Notch1 annotation to chemical synaptic transmission, postsynaptic. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0099565 chemical synaptic transmission, postsynaptic	IDA PMID:21315255 Activity-induced Notch signaling in neurons requires Arc/Arg...	KEEP AS NON CORE	Summary: Notch1 annotation to chemical synaptic transmission, postsynaptic. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007219 Notch signaling pathway	ISS GO_REF:0000024	ACCEPT	Summary: Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex. Reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x). Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007219 Notch signaling pathway	IMP PMID:14701881 Notch promotes epithelial-mesenchymal transition during card...	ACCEPT	Summary: Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex. Reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x). Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007219 Notch signaling pathway	IMP PMID:20007915 Distinct roles for cell-autonomous Notch signaling in cardio...	ACCEPT	Summary: Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex. Reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x). Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007219 Notch signaling pathway	IGI PMID:20890042 Integration of a Notch-dependent mesenchymal gene program an...	ACCEPT	Summary: Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex. Reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x). Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0061344 regulation of cell adhesion involved in heart morphogenesis	IMP PMID:14701881 Notch promotes epithelial-mesenchymal transition during card...	KEEP AS NON CORE	Summary: Notch1 regulates regulation of cell adhesion involved in heart morphogenesis. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0070168 negative regulation of biomineral tissue development	IMP PMID:26491108 Notch-Tnf signalling is required for development and homeost...	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of biomineral tissue development. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:22110751 Inhibitory role of Notch1 in calcific aortic valve disease.	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010008 endosome membrane	TAS Reactome:R-MMU-9793875	ACCEPT	Summary: Endosome membrane Reason: Notch1 trafficking. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010832 negative regulation of myotube differentiation	IMP PMID:18299578 Interaction with factor inhibiting HIF-1 defines an addition...	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of myotube differentiation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0050768 negative regulation of neurogenesis	IMP PMID:18299578 Interaction with factor inhibiting HIF-1 defines an addition...	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of neurogenesis. Reason: Neural development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0071456 cellular response to hypoxia	IDA PMID:18299578 Interaction with factor inhibiting HIF-1 defines an addition...	KEEP AS NON CORE	Summary: Notch1 is involved in cellular response to hypoxia. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0140537 transcription regulator activator activity	IDA PMID:18299578 Interaction with factor inhibiting HIF-1 defines an addition...	KEEP AS NON CORE	Summary: Notch1 annotation to transcription regulator activator activity. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0006357 regulation of transcription by RNA polymerase II	IMP PMID:20007915 Distinct roles for cell-autonomous Notch signaling in cardio...	KEEP AS NON CORE	Summary: Notch1 annotation to regulation of transcription by RNA polymerase II. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060379 cardiac muscle cell myoblast differentiation	IMP PMID:20007915 Distinct roles for cell-autonomous Notch signaling in cardio...	KEEP AS NON CORE	Summary: Notch1 regulates cardiac muscle cell myoblast differentiation. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:27719760 BLOS2 negatively regulates Notch signaling during neural and...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:18430783 Zfp64 participates in Notch signaling and regulates differen...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030163 protein catabolic process	IDA PMID:28561022 IL-17 induced NOTCH1 activation in oligodendrocyte progenito...	KEEP AS NON CORE	Summary: Notch1 annotation to protein catabolic process. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:28561022 IL-17 induced NOTCH1 activation in oligodendrocyte progenito...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0006606 protein import into nucleus	IDA PMID:28561022 IL-17 induced NOTCH1 activation in oligodendrocyte progenito...	KEEP AS NON CORE	Summary: Notch1 annotation to protein import into nucleus. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010467 gene expression	IDA PMID:28561022 IL-17 induced NOTCH1 activation in oligodendrocyte progenito...	KEEP AS NON CORE	Summary: Notch1 annotation to gene expression. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0072538 T-helper 17 type immune response	IDA PMID:28561022 IL-17 induced NOTCH1 activation in oligodendrocyte progenito...	KEEP AS NON CORE	Summary: Notch1 regulates t-helper 17 type immune response. Reason: T cell/immune development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0097400 interleukin-17-mediated signaling pathway	IDA PMID:28561022 IL-17 induced NOTCH1 activation in oligodendrocyte progenito...	KEEP AS NON CORE	Summary: Notch1 annotation to interleukin-17-mediated signaling pathway. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007221 positive regulation of transcription of Notch receptor target	IGI PMID:12794108 Notch-regulated ankyrin-repeat protein inhibits Notch1 signa...	ACCEPT	Summary: Positive regulation of transcription of Notch receptor target Reason: Core downstream function of NICD. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007221 positive regulation of transcription of Notch receptor target	IGI PMID:23160044 BCL6 controls neurogenesis through Sirt1-dependent epigeneti...	ACCEPT	Summary: Positive regulation of transcription of Notch receptor target Reason: Core downstream function of NICD. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003713 transcription coactivator activity	IDA PMID:17658278 Notch directly regulates Gata3 expression during T helper 2 ...	ACCEPT	Summary: NICD functions as a transcriptional coactivator by converting RBPJ from a repressor to an activator. Reason: Transcription coactivator activity is a core molecular function of NICD. It recruits MAML and displaces corepressors from RBPJ. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003713 transcription coactivator activity	IDA PMID:9111338 RBP-L, a transcription factor related to RBP-Jkappa.	ACCEPT	Summary: NICD functions as a transcriptional coactivator by converting RBPJ from a repressor to an activator. Reason: Transcription coactivator activity is a core molecular function of NICD. It recruits MAML and displaces corepressors from RBPJ. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003713 transcription coactivator activity	IDA PMID:17336907 Notch signaling is essential for ventricular chamber develop...	ACCEPT	Summary: NICD functions as a transcriptional coactivator by converting RBPJ from a repressor to an activator. Reason: Transcription coactivator activity is a core molecular function of NICD. It recruits MAML and displaces corepressors from RBPJ. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:24667410 Notch4 reveals a novel mechanism regulating Notch signal tra...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0070168 negative regulation of biomineral tissue development	IDA PMID:23583836 Endothelial nitric oxide signaling regulates Notch1 in aorti...	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of biomineral tissue development. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:17336907 Notch signaling is essential for ventricular chamber develop...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0120163 negative regulation of cold-induced thermogenesis	IMP PMID:25038826 Inhibition of Notch signaling promotes browning of white adi...	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of cold-induced thermogenesis. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003180 aortic valve morphogenesis	IMP PMID:26491108 Notch-Tnf signalling is required for development and homeost...	KEEP AS NON CORE	Summary: Notch1 is essential for aortic valve development. Notch1 mutations cause aortic valve disease (AOVD1). Reason: Strongly supported by mouse genetics - Notch1 mutations cause bicuspid aortic valve and calcific aortic valve disease (OMIM:109730). This is a key developmental phenotype but tissue-specific. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003182 coronary sinus valve morphogenesis	IMP PMID:26491108 Notch-Tnf signalling is required for development and homeost...	KEEP AS NON CORE	Summary: Notch1 regulates coronary sinus valve development. Reason: Highly specialized cardiac structure - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003184 pulmonary valve morphogenesis	IMP PMID:26491108 Notch-Tnf signalling is required for development and homeost...	KEEP AS NON CORE	Summary: Notch1 regulates pulmonary valve development. Mouse Notch1 mutations cause pulmonary valve abnormalities. Reason: Cardiac valve development - tissue-specific developmental function supported by mouse genetics. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003332 negative regulation of extracellular matrix constituent secretion	IMP PMID:26491108 Notch-Tnf signalling is required for development and homeost...	KEEP AS NON CORE	Summary: Notch1 negatively regulates ECM secretion in certain contexts. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	IDA PMID:26491108 Notch-Tnf signalling is required for development and homeost...	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010614 negative regulation of cardiac muscle hypertrophy	IMP PMID:26491108 Notch-Tnf signalling is required for development and homeost...	KEEP AS NON CORE	Summary: Notch1 regulates negative regulation of cardiac muscle hypertrophy. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060412 ventricular septum morphogenesis	IMP PMID:26491108 Notch-Tnf signalling is required for development and homeost...	KEEP AS NON CORE	Summary: Notch1 annotation to ventricular septum morphogenesis. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:1902339 positive regulation of apoptotic process involved in morphogenesis	IDA PMID:26491108 Notch-Tnf signalling is required for development and homeost...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of apoptotic process involved in morphogenesis. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003180 aortic valve morphogenesis	IGI PMID:27107132 Endothelial Notch1 Is Required for Proper Development of the...	KEEP AS NON CORE	Summary: Notch1 is essential for aortic valve development. Notch1 mutations cause aortic valve disease (AOVD1). Reason: Strongly supported by mouse genetics - Notch1 mutations cause bicuspid aortic valve and calcific aortic valve disease (OMIM:109730). This is a key developmental phenotype but tissue-specific. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003184 pulmonary valve morphogenesis	IGI PMID:27107132 Endothelial Notch1 Is Required for Proper Development of the...	KEEP AS NON CORE	Summary: Notch1 regulates pulmonary valve development. Mouse Notch1 mutations cause pulmonary valve abnormalities. Reason: Cardiac valve development - tissue-specific developmental function supported by mouse genetics. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003203 endocardial cushion morphogenesis	IGI PMID:27107132 Endothelial Notch1 Is Required for Proper Development of the...	KEEP AS NON CORE	Summary: Notch1 is required for endocardial cushion development which gives rise to heart valves. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0048873 homeostasis of number of cells within a tissue	IGI PMID:27107132 Endothelial Notch1 Is Required for Proper Development of the...	KEEP AS NON CORE	Summary: Notch1 annotation to homeostasis of number of cells within a tissue. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060412 ventricular septum morphogenesis	IGI PMID:27107132 Endothelial Notch1 Is Required for Proper Development of the...	KEEP AS NON CORE	Summary: Notch1 annotation to ventricular septum morphogenesis. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003180 aortic valve morphogenesis	IGI PMID:23583836 Endothelial nitric oxide signaling regulates Notch1 in aorti...	KEEP AS NON CORE	Summary: Notch1 is essential for aortic valve development. Notch1 mutations cause aortic valve disease (AOVD1). Reason: Strongly supported by mouse genetics - Notch1 mutations cause bicuspid aortic valve and calcific aortic valve disease (OMIM:109730). This is a key developmental phenotype but tissue-specific. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005634 nucleus	IDA PMID:23583836 Endothelial nitric oxide signaling regulates Notch1 in aorti...	ACCEPT	Summary: The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription. Reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010628 positive regulation of gene expression	IGI PMID:23583836 Endothelial nitric oxide signaling regulates Notch1 in aorti...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of gene expression. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:28089369 Deciphering the Fringe-Mediated Notch Code: Identification o...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:28498977 Consequences of MEGF10 deficiency on myoblast function and N...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0048845 venous blood vessel morphogenesis	IMP PMID:18952909 Artery and vein size is balanced by Notch and ephrin B2/EphB...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in venous blood vessel morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:1903849 positive regulation of aorta morphogenesis	IMP PMID:18952909 Artery and vein size is balanced by Notch and ephrin B2/EphB...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in positive regulation of aorta morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010468 regulation of gene expression	IMP PMID:11076679 Oscillating expression of c-Hey2 in the presomitic mesoderm ...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in regulation of gene expression, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:21191019 A protein (ORF2) encoded by the latency-related gene of bovi...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045070 positive regulation of viral genome replication	IMP PMID:21191019 A protein (ORF2) encoded by the latency-related gene of bovi...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of viral genome replication. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003197 endocardial cushion development	IMP PMID:14701881 Notch promotes epithelial-mesenchymal transition during card...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in endocardial cushion development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:21985982 Delta-like 1-Lysine613 regulates notch signaling.	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:18676613 The intracellular region of Notch ligands Dll1 and Dll3 regu...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:24715457 Cadherin-based adhesions in the apical endfoot are required ...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005912 adherens junction	IDA PMID:24715457 Cadherin-based adhesions in the apical endfoot are required ...	KEEP AS NON CORE	Summary: Notch1 annotation to adherens junction. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0016324 apical plasma membrane	IDA PMID:24715457 Cadherin-based adhesions in the apical endfoot are required ...	KEEP AS NON CORE	Summary: Notch1 annotation to apical plasma membrane. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:12050162 The nephroblastoma overexpressed gene (NOV/ccn3) protein ass...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0006357 regulation of transcription by RNA polymerase II	IMP PMID:25535395 Notch inhibition induces mitotically generated hair cells in...	KEEP AS NON CORE	Summary: Notch1 annotation to regulation of transcription by RNA polymerase II. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0008285 negative regulation of cell population proliferation	IMP PMID:25535395 Notch inhibition induces mitotically generated hair cells in...	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of cell population proliferation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0042127 regulation of cell population proliferation	IGI PMID:25535395 Notch inhibition induces mitotically generated hair cells in...	KEEP AS NON CORE	Summary: Notch1 annotation to regulation of cell population proliferation. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045607 regulation of inner ear auditory receptor cell differentiation	IMP PMID:25535395 Notch inhibition induces mitotically generated hair cells in...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in regulation of inner ear auditory receptor cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045608 negative regulation of inner ear auditory receptor cell differentiation	IMP PMID:25535395 Notch inhibition induces mitotically generated hair cells in...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in negative regulation of inner ear auditory receptor cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0090090 negative regulation of canonical Wnt signaling pathway	IMP PMID:25535395 Notch inhibition induces mitotically generated hair cells in...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in negative regulation of canonical Wnt signaling pathway, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005112 Notch binding	IPI PMID:24667410 Notch4 reveals a novel mechanism regulating Notch signal tra...	ACCEPT	Summary: Notch1 can bind other Notch family members, potentially in cis-inhibition or heterodimer formation. Reason: Notch receptors can interact with each other. The identical protein binding annotation (GO:0042802) already captures homodimerization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005783 endoplasmic reticulum	IDA PMID:24667410 Notch4 reveals a novel mechanism regulating Notch signal tra...	ACCEPT	Summary: Endoplasmic reticulum Reason: Notch1 synthesis and maturation. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	IDA PMID:24667410 Notch4 reveals a novel mechanism regulating Notch signal tra...	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0008593 regulation of Notch signaling pathway	IGI PMID:24667410 Notch4 reveals a novel mechanism regulating Notch signal tra...	ACCEPT	Summary: regulation of Notch signaling pathway is consistent with canonical mouse Notch1 receptor biology. Reason: Falcon synthesis identifies the conserved Notch1 mechanism as ER/Golgi maturation, plasma-membrane ligand reception, regulated proteolysis, NICD nuclear entry, and CSL/RBPJ-MAML transcriptional activation. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0031410 cytoplasmic vesicle	IDA PMID:24667410 Notch4 reveals a novel mechanism regulating Notch signal tra...	KEEP AS NON CORE	Summary: Notch1 annotation to cytoplasmic vesicle. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045747 positive regulation of Notch signaling pathway	IDA PMID:24667410 Notch4 reveals a novel mechanism regulating Notch signal tra...	ACCEPT	Summary: positive regulation of Notch signaling pathway is consistent with canonical mouse Notch1 receptor biology. Reason: Falcon synthesis identifies the conserved Notch1 mechanism as ER/Golgi maturation, plasma-membrane ligand reception, regulated proteolysis, NICD nuclear entry, and CSL/RBPJ-MAML transcriptional activation. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0071944 cell periphery	IDA PMID:23284756 Ascl1 (Mash1) knockout perturbs differentiation of nonneuron...	KEEP AS NON CORE	Summary: Notch1 annotation to cell periphery. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0043235 receptor complex	ISO PMID:23382219 Structural basis for endosomal trafficking of diverse transm...	ACCEPT	Summary: Notch1 exists as a heterodimeric receptor complex formed by furin cleavage during maturation. The N(EC) and N(TM) fragments remain associated at the cell surface. Reason: Notch1 forms a heterodimeric complex after S1 furin cleavage in the Golgi. The extracellular and transmembrane fragments are non-covalently associated. This is well-documented in UniProt and structural studies. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060271 cilium assembly	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Notch1 annotation to cilium assembly. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:1902263 apoptotic process involved in embryonic digit morphogenesis	IMP PMID:16245338 Notch1 signals through Jagged2 to regulate apoptosis in the ...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in apoptotic process involved in embryonic digit morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0001726 ruffle	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in ruffle, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005856 cytoskeleton	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in cytoskeleton, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030027 lamellipodium	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in lamellipodium, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0008285 negative regulation of cell population proliferation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of cell population proliferation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0035148 tube formation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Notch1 annotation to tube formation. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0035924 cellular response to vascular endothelial growth factor stimulus	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Notch1 regulates cellular response to vascular endothelial growth factor stimulus. Reason: Vascular development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0090051 negative regulation of cell migration involved in sprouting angiogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Notch1 regulates negative regulation of cell migration involved in sprouting angiogenesis. Reason: Vascular development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:2001027 negative regulation of endothelial cell chemotaxis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Notch1 regulates negative regulation of endothelial cell chemotaxis. Reason: Vascular development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0035914 skeletal muscle cell differentiation	IMP PMID:22147266 Analysis of early C2C12 myogenesis identifies stably and dif...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in skeletal muscle cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005634 nucleus	IDA PMID:17685488 Monitoring Notch1 activity in development: evidence for a fe...	ACCEPT	Summary: The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription. Reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:14701881 Notch promotes epithelial-mesenchymal transition during card...	KEEP AS NON CORE	Summary: Notch1 can negatively regulate certain genes through target gene specificity and crosstalk with repressive mechanisms. Reason: While Notch1 primarily activates transcription, it can also lead to repression of certain targets depending on context. This is a secondary regulatory outcome. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.	KEEP AS NON CORE	Summary: Notch1 can negatively regulate certain genes through target gene specificity and crosstalk with repressive mechanisms. Reason: While Notch1 primarily activates transcription, it can also lead to repression of certain targets depending on context. This is a secondary regulatory outcome. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005634 nucleus	IMP PMID:20007915 Distinct roles for cell-autonomous Notch signaling in cardio...	ACCEPT	Summary: The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription. Reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:14701881 Notch promotes epithelial-mesenchymal transition during card...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:17303760 Combined loss of Hey1 and HeyL causes congenital heart defec...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:20007915 Distinct roles for cell-autonomous Notch signaling in cardio...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003180 aortic valve morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Notch1 is essential for aortic valve development. Notch1 mutations cause aortic valve disease (AOVD1). Reason: Strongly supported by mouse genetics - Notch1 mutations cause bicuspid aortic valve and calcific aortic valve disease (OMIM:109730). This is a key developmental phenotype but tissue-specific. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003213 cardiac right atrium morphogenesis	IMP PMID:20007915 Distinct roles for cell-autonomous Notch signaling in cardio...	KEEP AS NON CORE	Summary: Notch1 regulates right atrium morphogenesis. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003241 growth involved in heart morphogenesis	IMP PMID:20007915 Distinct roles for cell-autonomous Notch signaling in cardio...	KEEP AS NON CORE	Summary: Notch1 regulates growth during cardiac morphogenesis. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0014031 mesenchymal cell development	IMP PMID:17303760 Combined loss of Hey1 and HeyL causes congenital heart defec...	KEEP AS NON CORE	Summary: Notch1 promotes mesenchymal cell development. Reason: EMT regulation - context-dependent function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030279 negative regulation of ossification	IMP PMID:21493891 Diet-induced aortic valve disease in mice haploinsufficient ...	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of ossification. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045892 negative regulation of DNA-templated transcription	IMP PMID:19695258 Notch1 represses osteogenic pathways in aortic valve cells.	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of dna-templated transcription. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:15107403 The Notch target genes Hey1 and Hey2 are required for embryo...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0055008 cardiac muscle tissue morphogenesis	IMP PMID:20007915 Distinct roles for cell-autonomous Notch signaling in cardio...	KEEP AS NON CORE	Summary: Notch1 regulates cardiac muscle tissue morphogenesis. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060045 positive regulation of cardiac muscle cell proliferation	IMP PMID:20007915 Distinct roles for cell-autonomous Notch signaling in cardio...	KEEP AS NON CORE	Summary: Notch1 regulates positive regulation of cardiac muscle cell proliferation. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060317 cardiac epithelial to mesenchymal transition	IMP PMID:17303760 Combined loss of Hey1 and HeyL causes congenital heart defec...	KEEP AS NON CORE	Summary: Notch1 regulates cardiac epithelial to mesenchymal transition. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060411 cardiac septum morphogenesis	IMP PMID:20007915 Distinct roles for cell-autonomous Notch signaling in cardio...	KEEP AS NON CORE	Summary: Notch1 regulates cardiac septum morphogenesis. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060842 arterial endothelial cell differentiation	IMP PMID:15107403 The Notch target genes Hey1 and Hey2 are required for embryo...	KEEP AS NON CORE	Summary: Notch1 regulates arterial endothelial cell differentiation. Reason: Vascular development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:20890042 Integration of a Notch-dependent mesenchymal gene program an...	KEEP AS NON CORE	Summary: Notch1 can negatively regulate certain genes through target gene specificity and crosstalk with repressive mechanisms. Reason: While Notch1 primarily activates transcription, it can also lead to repression of certain targets depending on context. This is a secondary regulatory outcome. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0001947 heart looping	IGI PMID:12730124 Notch signaling regulates left-right asymmetry determination...	KEEP AS NON CORE	Summary: Notch1 is required for proper cardiac morphogenesis including heart looping during development. Reason: Heart looping is a specific developmental process. Notch1 mutations cause congenital heart defects (AOVD1), confirming cardiac development roles, but this is tissue-specific. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003160 endocardium morphogenesis	IMP PMID:20890042 Integration of a Notch-dependent mesenchymal gene program an...	KEEP AS NON CORE	Summary: Notch1 regulates endocardium morphogenesis during heart development. Reason: Related to cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003162 atrioventricular node development	IMP PMID:21266778 Notch signaling regulates murine atrioventricular conduction...	KEEP AS NON CORE	Summary: Notch1 is involved in development of cardiac conduction system components. Reason: Specialized cardiac developmental process. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003169 coronary vein morphogenesis	IMP PMID:21311046 Differential Notch signaling in the epicardium is required f...	KEEP AS NON CORE	Summary: Notch1 regulates coronary vessel development including vein morphogenesis. Reason: Cardiac/vascular development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003181 atrioventricular valve morphogenesis	IMP PMID:14701881 Notch promotes epithelial-mesenchymal transition during card...	KEEP AS NON CORE	Summary: Notch1 regulates AV valve development through endocardial cushion formation. Reason: Cardiac valve development - tissue-specific developmental function supported by mouse studies. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003181 atrioventricular valve morphogenesis	IMP PMID:21266778 Notch signaling regulates murine atrioventricular conduction...	KEEP AS NON CORE	Summary: Notch1 regulates AV valve development through endocardial cushion formation. Reason: Cardiac valve development - tissue-specific developmental function supported by mouse studies. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003198 epithelial to mesenchymal transition involved in endocardial cushion formation	IMP PMID:14701881 Notch promotes epithelial-mesenchymal transition during card...	KEEP AS NON CORE	Summary: Notch1 promotes EMT during endocardial cushion formation, essential for valve development. Reason: EMT in heart development is well-documented for Notch1. Tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003203 endocardial cushion morphogenesis	IMP PMID:14701881 Notch promotes epithelial-mesenchymal transition during card...	KEEP AS NON CORE	Summary: Notch1 is required for endocardial cushion development which gives rise to heart valves. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003207 cardiac chamber formation	IMP PMID:20890042 Integration of a Notch-dependent mesenchymal gene program an...	KEEP AS NON CORE	Summary: Notch1 regulates cardiac chamber formation during heart development. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003208 cardiac ventricle morphogenesis	IMP PMID:21311046 Differential Notch signaling in the epicardium is required f...	KEEP AS NON CORE	Summary: Notch1 regulates ventricular development. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003209 cardiac atrium morphogenesis	IMP PMID:20890042 Integration of a Notch-dependent mesenchymal gene program an...	KEEP AS NON CORE	Summary: Notch1 regulates atrial development. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003214 cardiac left ventricle morphogenesis	IMP PMID:20890042 Integration of a Notch-dependent mesenchymal gene program an...	KEEP AS NON CORE	Summary: Notch1 regulates left ventricle morphogenesis. Relevant to hypoplastic left heart syndrome. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003273 cell migration involved in endocardial cushion formation	IMP PMID:20890042 Integration of a Notch-dependent mesenchymal gene program an...	KEEP AS NON CORE	Summary: Notch1 regulates cell migration during endocardial cushion formation. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003344 pericardium morphogenesis	IMP PMID:14701881 Notch promotes epithelial-mesenchymal transition during card...	KEEP AS NON CORE	Summary: Notch1 regulates pericardium development. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003344 pericardium morphogenesis	IMP PMID:20890042 Integration of a Notch-dependent mesenchymal gene program an...	KEEP AS NON CORE	Summary: Notch1 regulates pericardium development. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003344 pericardium morphogenesis	IMP PMID:21311046 Differential Notch signaling in the epicardium is required f...	KEEP AS NON CORE	Summary: Notch1 regulates pericardium development. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010718 positive regulation of epithelial to mesenchymal transition	IMP PMID:20890042 Integration of a Notch-dependent mesenchymal gene program an...	KEEP AS NON CORE	Summary: Notch1 promotes positive regulation of epithelial to mesenchymal transition. Reason: EMT regulation - context-dependent function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030334 regulation of cell migration	IMP PMID:20890042 Integration of a Notch-dependent mesenchymal gene program an...	KEEP AS NON CORE	Summary: Notch1 annotation to regulation of cell migration. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030335 positive regulation of cell migration	IMP PMID:20890042 Integration of a Notch-dependent mesenchymal gene program an...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of cell migration. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:21311046 Differential Notch signaling in the epicardium is required f...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060038 cardiac muscle cell proliferation	IMP PMID:21311046 Differential Notch signaling in the epicardium is required f...	KEEP AS NON CORE	Summary: Notch1 regulates cardiac muscle cell proliferation. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060843 venous endothelial cell differentiation	IMP PMID:20890042 Integration of a Notch-dependent mesenchymal gene program an...	KEEP AS NON CORE	Summary: Notch1 regulates venous endothelial cell differentiation. Reason: Vascular development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060948 cardiac vascular smooth muscle cell development	IMP PMID:21311046 Differential Notch signaling in the epicardium is required f...	KEEP AS NON CORE	Summary: Notch1 regulates cardiac vascular smooth muscle cell development. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060956 endocardial cell differentiation	IMP PMID:20890042 Integration of a Notch-dependent mesenchymal gene program an...	KEEP AS NON CORE	Summary: Notch1 annotation to endocardial cell differentiation. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060979 vasculogenesis involved in coronary vascular morphogenesis	IMP PMID:21311046 Differential Notch signaling in the epicardium is required f...	KEEP AS NON CORE	Summary: Notch1 regulates vasculogenesis involved in coronary vascular morphogenesis. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060982 coronary artery morphogenesis	IMP PMID:21311046 Differential Notch signaling in the epicardium is required f...	KEEP AS NON CORE	Summary: Notch1 regulates coronary artery morphogenesis. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0061384 heart trabecula morphogenesis	IMP PMID:20890042 Integration of a Notch-dependent mesenchymal gene program an...	KEEP AS NON CORE	Summary: Notch1 regulates heart trabecula morphogenesis. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0070986 left/right axis specification	IGI PMID:12730124 Notch signaling regulates left-right asymmetry determination...	KEEP AS NON CORE	Summary: Notch1 annotation to left/right axis specification. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:1901201 regulation of extracellular matrix assembly	IMP PMID:21311046 Differential Notch signaling in the epicardium is required f...	KEEP AS NON CORE	Summary: Notch1 annotation to regulation of extracellular matrix assembly. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005634 nucleus	IDA PMID:17336907 Notch signaling is essential for ventricular chamber develop...	ACCEPT	Summary: The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription. Reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:1901189 positive regulation of ephrin receptor signaling pathway	IC PMID:17336907 Notch signaling is essential for ventricular chamber develop...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in positive regulation of ephrin receptor signaling pathway, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003157 endocardium development	IMP PMID:17336907 Notch signaling is essential for ventricular chamber develop...	KEEP AS NON CORE	Summary: Notch1 is essential for endocardium development and endocardial cell differentiation. Reason: Cardiac development is a well-established Notch1 function based on mouse disease genetics (AOVD1, AOS5), but represents tissue-specific developmental role. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003222 ventricular trabecula myocardium morphogenesis	IMP PMID:17336907 Notch signaling is essential for ventricular chamber develop...	KEEP AS NON CORE	Summary: Notch1 regulates trabeculation of the ventricular myocardium. Reason: Cardiac development - tissue-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005654 nucleoplasm	TAS Reactome:R-MMU-4396387	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005654 nucleoplasm	TAS Reactome:R-MMU-9667655	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005654 nucleoplasm	TAS Reactome:R-MMU-9824206	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005654 nucleoplasm	TAS Reactome:R-MMU-9824230	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005654 nucleoplasm	TAS Reactome:R-MMU-9824231	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005654 nucleoplasm	TAS Reactome:R-MMU-9824278	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005654 nucleoplasm	TAS Reactome:R-NUL-2064853	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005654 nucleoplasm	TAS Reactome:R-NUL-2064883	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005654 nucleoplasm	TAS Reactome:R-NUL-2065560	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005654 nucleoplasm	TAS Reactome:R-NUL-4396363	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005829 cytosol	TAS Reactome:R-MMU-2067638	ACCEPT	Summary: Cytosol Reason: NICD released to cytosol before nuclear import. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005829 cytosol	TAS Reactome:R-MMU-209285	ACCEPT	Summary: Cytosol Reason: NICD released to cytosol before nuclear import. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005829 cytosol	TAS Reactome:R-NUL-2065902	ACCEPT	Summary: Cytosol Reason: NICD released to cytosol before nuclear import. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0019899 enzyme binding	IPI PMID:17573339 Asparaginyl hydroxylation of the Notch ankyrin repeat domain...	ACCEPT	Summary: Enzyme binding Reason: Notch1 binds enzymes involved in its processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0019899 enzyme binding	IPI PMID:18299578 Interaction with factor inhibiting HIF-1 defines an addition...	ACCEPT	Summary: Enzyme binding Reason: Notch1 binds enzymes involved in its processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:19245366 MYPT1, the targeting subunit of smooth-muscle myosin phospha...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0004857 enzyme inhibitor activity	IDA PMID:17573339 Asparaginyl hydroxylation of the Notch ankyrin repeat domain...	KEEP AS NON CORE	Summary: The Notch1 ankyrin-repeat domain can inhibit factor inhibiting HIF (FIH) in vitro, but this is a context-specific biochemical interaction rather than the core Notch receptor function. Reason: PMID:17573339 reports that Notch ankyrin-repeat domains compete with HIF for FIH-dependent hydroxylation and proposes ARD proteins as natural FIH inhibitors. Retain the term as supported non-core biochemistry, distinct from canonical Notch ligand-receptor signaling and NICD transcriptional coactivation. Supporting Evidence: PMID:17573339 ARD proteins were found to efficiently compete with HIF for FIH-dependent hydroxylation file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon synthesis identifies Notch1 core function as ligand-triggered receptor cleavage and NICD/CSL/MAML transcriptional signaling; FIH inhibition is peripheral.]
GO:0005634 nucleus	IDA PMID:18299578 Interaction with factor inhibiting HIF-1 defines an addition...	ACCEPT	Summary: The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription. Reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007219 Notch signaling pathway	IDA PMID:21419176 The EGF-like proteins DLK1 and DLK2 function as inhibitory n...	ACCEPT	Summary: Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex. Reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x). Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0043086 negative regulation of catalytic activity	IDA PMID:17573339 Asparaginyl hydroxylation of the Notch ankyrin repeat domain...	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of catalytic activity. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005576 extracellular region	TAS Reactome:R-MMU-2053938	KEEP AS NON CORE	Summary: Notch1 annotation to extracellular region. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005576 extracellular region	TAS Reactome:R-MMU-2053963	KEEP AS NON CORE	Summary: Notch1 annotation to extracellular region. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005576 extracellular region	TAS Reactome:R-MMU-2066712	KEEP AS NON CORE	Summary: Notch1 annotation to extracellular region. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005576 extracellular region	TAS Reactome:R-MMU-2067638	KEEP AS NON CORE	Summary: Notch1 annotation to extracellular region. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005576 extracellular region	TAS Reactome:R-MMU-2071906	KEEP AS NON CORE	Summary: Notch1 annotation to extracellular region. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005576 extracellular region	TAS Reactome:R-MMU-2077477	KEEP AS NON CORE	Summary: Notch1 annotation to extracellular region. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005576 extracellular region	TAS Reactome:R-MMU-2077479	KEEP AS NON CORE	Summary: Notch1 annotation to extracellular region. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005576 extracellular region	TAS Reactome:R-NUL-2065902	KEEP AS NON CORE	Summary: Notch1 annotation to extracellular region. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005576 extracellular region	TAS Reactome:R-NUL-209162	KEEP AS NON CORE	Summary: Notch1 annotation to extracellular region. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0000139 Golgi membrane	TAS Reactome:R-MMU-2023158	ACCEPT	Summary: Notch1 undergoes S1 cleavage by furin in the trans-Golgi network during maturation, converting the precursor into the functional heterodimer. Reason: Golgi membrane localization is part of the Notch1 biosynthetic pathway. UniProt states the precursor is proteolytically cleaved by furin-like convertase in the trans-Golgi network before reaching the plasma membrane. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0000139 Golgi membrane	TAS Reactome:R-MMU-2032750	ACCEPT	Summary: Notch1 undergoes S1 cleavage by furin in the trans-Golgi network during maturation, converting the precursor into the functional heterodimer. Reason: Golgi membrane localization is part of the Notch1 biosynthetic pathway. UniProt states the precursor is proteolytically cleaved by furin-like convertase in the trans-Golgi network before reaching the plasma membrane. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-MMU-2023179	ACCEPT	Summary: Notch1 is synthesized and begins its maturation in the ER membrane before trafficking to the Golgi. Reason: ER membrane localization is part of the Notch1 biosynthetic pathway. UniProt notes synthesis in the endoplasmic reticulum as an inactive form. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-MMU-2032750	ACCEPT	Summary: Notch1 is synthesized and begins its maturation in the ER membrane before trafficking to the Golgi. Reason: ER membrane localization is part of the Notch1 biosynthetic pathway. UniProt notes synthesis in the endoplasmic reticulum as an inactive form. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-MMU-9824249	ACCEPT	Summary: Notch1 is synthesized and begins its maturation in the ER membrane before trafficking to the Golgi. Reason: ER membrane localization is part of the Notch1 biosynthetic pathway. UniProt notes synthesis in the endoplasmic reticulum as an inactive form. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-NUL-1986584	ACCEPT	Summary: Notch1 is synthesized and begins its maturation in the ER membrane before trafficking to the Golgi. Reason: ER membrane localization is part of the Notch1 biosynthetic pathway. UniProt notes synthesis in the endoplasmic reticulum as an inactive form. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	TAS Reactome:R-MMU-209285	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	TAS Reactome:R-NUL-2063915	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	TAS Reactome:R-NUL-209162	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	TAS Reactome:R-MMU-2053938	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:15574878 Fringe glycosyltransferases differentially modulate Notch1 p...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0009986 cell surface	IDA PMID:15574878 Fringe glycosyltransferases differentially modulate Notch1 p...	ACCEPT	Summary: Notch1 is expressed at the cell surface where it functions as a receptor for trans-acting ligands on neighboring cells. Reason: Cell surface localization is essential for Notch1 receptor function. The extracellular domain (N(EC)) binds ligands at the cell surface, triggering the proteolytic cascade. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0002437 inflammatory response to antigenic stimulus	IGI PMID:17658279 Direct regulation of Gata3 expression determines the T helpe...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in inflammatory response to antigenic stimulus, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0006959 humoral immune response	IGI PMID:17658279 Direct regulation of Gata3 expression determines the T helpe...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in humoral immune response, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003219 cardiac right ventricle formation	IMP PMID:19620969 A regulatory pathway involving Notch1/beta-catenin/Isl1 dete...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in cardiac right ventricle formation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007219 Notch signaling pathway	IMP PMID:19620969 A regulatory pathway involving Notch1/beta-catenin/Isl1 dete...	ACCEPT	Summary: Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex. Reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x). Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0090090 negative regulation of canonical Wnt signaling pathway	IMP PMID:19620969 A regulatory pathway involving Notch1/beta-catenin/Isl1 dete...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in negative regulation of canonical Wnt signaling pathway, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:20547764 ZFP423 coordinates Notch and bone morphogenetic protein sign...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030513 positive regulation of BMP signaling pathway	IDA PMID:20547764 ZFP423 coordinates Notch and bone morphogenetic protein sign...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of bmp signaling pathway. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045893 positive regulation of DNA-templated transcription	IDA PMID:20547764 ZFP423 coordinates Notch and bone morphogenetic protein sign...	ACCEPT	Summary: NICD positively regulates transcription by forming a coactivator complex with RBPJ and MAML that displaces corepressors. Reason: Notch1 NICD functions as a transcriptional activator. The NICD-RBPJ-MAML complex recruits coactivators like p300 to activate target gene transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:2000974 negative regulation of pro-B cell differentiation	IMP PMID:12032823 Overexpression of the Notch target genes Hes in vivo induces...	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of pro-b cell differentiation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT	IDA PMID:15156153 Hes binding to STAT3 mediates crosstalk between Notch and JA...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of receptor signaling pathway via jak-stat. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:12032823 Overexpression of the Notch target genes Hes in vivo induces...	KEEP AS NON CORE	Summary: Notch1 can negatively regulate certain genes through target gene specificity and crosstalk with repressive mechanisms. Reason: While Notch1 primarily activates transcription, it can also lead to repression of certain targets depending on context. This is a secondary regulatory outcome. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045893 positive regulation of DNA-templated transcription	IDA PMID:12666205 Hes1 but not Hes5 regulates an astrocyte versus oligodendroc...	ACCEPT	Summary: NICD positively regulates transcription by forming a coactivator complex with RBPJ and MAML that displaces corepressors. Reason: Notch1 NICD functions as a transcriptional activator. The NICD-RBPJ-MAML complex recruits coactivators like p300 to activate target gene transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0048711 positive regulation of astrocyte differentiation	IDA PMID:12666205 Hes1 but not Hes5 regulates an astrocyte versus oligodendroc...	KEEP AS NON CORE	Summary: Notch1 positively regulates astrocyte differentiation via HES/HEY transcriptional targets. Reason: Positive regulation of astrocyte differentiation is a supported downstream neural-lineage output of Notch1 signaling, but it is not the general core receptor/NICD transcription function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0048715 negative regulation of oligodendrocyte differentiation	IDA PMID:12666205 Hes1 but not Hes5 regulates an astrocyte versus oligodendroc...	KEEP AS NON CORE	Summary: Notch1 negatively regulates oligodendrocyte differentiation, favoring astrocyte fate. Reason: Negative regulation of oligodendrocyte differentiation is a neural-lineage output of Notch1 signaling and should be retained as non-core rather than as the defining receptor/NICD function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060253 negative regulation of glial cell proliferation	IDA PMID:12666205 Hes1 but not Hes5 regulates an astrocyte versus oligodendroc...	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of glial cell proliferation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0072017 distal tubule development	IEP PMID:15821257 Segmental expression of Notch and Hairy genes in nephrogenes...	KEEP AS NON CORE	Summary: Notch1 annotation to distal tubule development. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0072044 collecting duct development	IEP PMID:15821257 Segmental expression of Notch and Hairy genes in nephrogenes...	KEEP AS NON CORE	Summary: Notch1 annotation to collecting duct development. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0072144 glomerular mesangial cell development	IEP PMID:15821257 Segmental expression of Notch and Hairy genes in nephrogenes...	KEEP AS NON CORE	Summary: Notch1 annotation to glomerular mesangial cell development. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007219 Notch signaling pathway	IMP PMID:19154718 Hey2 regulation by FGF provides a Notch-independent mechanis...	ACCEPT	Summary: Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex. Reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x). Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0009912 auditory receptor cell fate commitment	IMP PMID:19154718 Hey2 regulation by FGF provides a Notch-independent mechanis...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in auditory receptor cell fate commitment, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045665 negative regulation of neuron differentiation	IGI PMID:10205173 Hes1 and Hes5 as notch effectors in mammalian neuronal diffe...	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of neuron differentiation via Notch-mediated lateral inhibition, a canonical function in the neuron-glia binary fate decision. Reason: Notch1-mediated effects on neuron differentiation are well-supported developmental outputs, but they are tissue-context consequences of the core juxtacrine receptor/NICD transcription mechanism rather than the core function itself. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045955 negative regulation of calcium ion-dependent exocytosis	IMP PMID:19251639 Notch and Wnt signals cooperatively control cell proliferati...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in negative regulation of calcium ion-dependent exocytosis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0050679 positive regulation of epithelial cell proliferation	IGI PMID:19251639 Notch and Wnt signals cooperatively control cell proliferati...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in positive regulation of epithelial cell proliferation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0032495 response to muramyl dipeptide	IDA PMID:21156799 Intracellular pathogen sensor NOD2 programs macrophages to t...	KEEP AS NON CORE	Summary: Notch1 is involved in response to muramyl dipeptide. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030514 negative regulation of BMP signaling pathway	IMP PMID:19695258 Notch1 represses osteogenic pathways in aortic valve cells.	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of bmp signaling pathway. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045668 negative regulation of osteoblast differentiation	IMP PMID:19695258 Notch1 represses osteogenic pathways in aortic valve cells.	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of osteoblast differentiation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0002051 osteoblast fate commitment	NAS PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in osteoblast fate commitment, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003160 endocardium morphogenesis	IEP PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.	KEEP AS NON CORE	Summary: Notch1 regulates endocardium morphogenesis during heart development. Reason: Related to cardiac development - tissue-specific developmental function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045892 negative regulation of DNA-templated transcription	IDA PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of dna-templated transcription. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060528 secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development	IMP PMID:16360140 Notch signaling is required for normal prostatic epithelial ...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060740 prostate gland epithelium morphogenesis	IMP PMID:16360140 Notch signaling is required for normal prostatic epithelial ...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in prostate gland epithelium morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0060768 regulation of epithelial cell proliferation involved in prostate gland development	IMP PMID:16360140 Notch signaling is required for normal prostatic epithelial ...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in regulation of epithelial cell proliferation involved in prostate gland development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0001701 in utero embryonic development	IMP PMID:7789282 Notch1 is required for the coordinate segmentation of somite...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in in utero embryonic development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007368 determination of left/right symmetry	IMP PMID:7789282 Notch1 is required for the coordinate segmentation of somite...	KEEP AS NON CORE	Summary: Notch1 annotation to determination of left/right symmetry. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0014807 regulation of somitogenesis	IMP PMID:7789282 Notch1 is required for the coordinate segmentation of somite...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in regulation of somitogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0021915 neural tube development	IMP PMID:7789282 Notch1 is required for the coordinate segmentation of somite...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in neural tube development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0043069 negative regulation of programmed cell death	IMP PMID:7789282 Notch1 is required for the coordinate segmentation of somite...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in negative regulation of programmed cell death, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005634 nucleus	IDA PMID:16324690 BMP7 inhibits branching morphogenesis in the prostate gland ...	ACCEPT	Summary: The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription. Reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045893 positive regulation of DNA-templated transcription	IDA PMID:9111338 RBP-L, a transcription factor related to RBP-Jkappa.	ACCEPT	Summary: NICD positively regulates transcription by forming a coactivator complex with RBPJ and MAML that displaces corepressors. Reason: Notch1 NICD functions as a transcriptional activator. The NICD-RBPJ-MAML complex recruits coactivators like p300 to activate target gene transcription. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:10958687 Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly in...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:9315665 Isolation and functional analysis of a cDNA for human Jagged...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0001889 liver development	IMP PMID:15226394 Notch signaling controls hepatoblast differentiation by alte...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in liver development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010468 regulation of gene expression	IMP PMID:9102301 Conservation of the Notch signalling pathway in mammalian ne...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in regulation of gene expression, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030182 neuron differentiation	IMP PMID:9102301 Conservation of the Notch signalling pathway in mammalian ne...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in neuron differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0050767 regulation of neurogenesis	IMP PMID:9102301 Conservation of the Notch signalling pathway in mammalian ne...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in regulation of neurogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	TAS Reactome:R-MMU-2053963	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	TAS Reactome:R-MMU-2066712	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	TAS Reactome:R-MMU-2067638	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	TAS Reactome:R-MMU-2071906	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	TAS Reactome:R-MMU-2077477	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	TAS Reactome:R-MMU-2077479	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	TAS Reactome:R-NUL-2065902	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005634 nucleus	IDA PMID:17079689 Canonical notch signaling functions as a commitment switch i...	ACCEPT	Summary: The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription. Reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	IDA PMID:17079689 Canonical notch signaling functions as a commitment switch i...	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045618 positive regulation of keratinocyte differentiation	IGI PMID:16618808 Cross-regulation between Notch and p63 in keratinocyte commi...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in positive regulation of keratinocyte differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045618 positive regulation of keratinocyte differentiation	IDA PMID:17079689 Canonical notch signaling functions as a commitment switch i...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in positive regulation of keratinocyte differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:16618808 Cross-regulation between Notch and p63 in keratinocyte commi...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IGI PMID:16618808 Cross-regulation between Notch and p63 in keratinocyte commi...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0031490 chromatin DNA binding	IDA PMID:17658278 Notch directly regulates Gata3 expression during T helper 2 ...	KEEP AS NON CORE	Summary: Notch1 annotation to chromatin DNA binding. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:17658278 Notch directly regulates Gata3 expression during T helper 2 ...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0046533 negative regulation of photoreceptor cell differentiation	IMP PMID:16452096 Notch 1 inhibits photoreceptor production in the developing ...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in negative regulation of photoreceptor cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005737 cytoplasm	IDA PMID:15965470 DNER acts as a neuron-specific Notch ligand during Bergmann ...	ACCEPT	Summary: Cytoplasm Reason: NICD transits through cytoplasm. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0010001 glial cell differentiation	IMP PMID:15965470 DNER acts as a neuron-specific Notch ligand during Bergmann ...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in glial cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005634 nucleus	IDA PMID:16607638 Jag2-Notch1 signaling regulates oral epithelial differentiat...	ACCEPT	Summary: The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription. Reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007440 foregut morphogenesis	IMP PMID:16107537 Direct regulation of intestinal fate by Notch.	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in foregut morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045165 cell fate commitment	IMP PMID:16107537 Direct regulation of intestinal fate by Notch.	ACCEPT	Summary: cell fate commitment is consistent with canonical mouse Notch1 receptor biology. Reason: Falcon synthesis identifies the conserved Notch1 mechanism as ER/Golgi maturation, plasma-membrane ligand reception, regulated proteolysis, NICD nuclear entry, and CSL/RBPJ-MAML transcriptional activation. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0050678 regulation of epithelial cell proliferation	IMP PMID:16107537 Direct regulation of intestinal fate by Notch.	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in regulation of epithelial cell proliferation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0002040 sprouting angiogenesis	IMP PMID:15809373 Essential role of endothelial Notch1 in angiogenesis.	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in sprouting angiogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0031069 hair follicle morphogenesis	IMP PMID:15978571 Notch1 is essential for postnatal hair follicle development ...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in hair follicle morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030326 embryonic limb morphogenesis	IGI PMID:16169548 Notch1 and 2 cooperate in limb ectoderm to receive an early ...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in embryonic limb morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0043065 positive regulation of apoptotic process	IGI PMID:16169548 Notch1 and 2 cooperate in limb ectoderm to receive an early ...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in positive regulation of apoptotic process, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0035116 embryonic hindlimb morphogenesis	IMP PMID:16245338 Notch1 signals through Jagged2 to regulate apoptosis in the ...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in embryonic hindlimb morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:16145673 Fjx1: a notch-inducible secreted ligand with specific bindin...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0048754 branching morphogenesis of an epithelial tube	IMP PMID:15064243 Functional diversity of notch family genes in fetal lung dev...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in branching morphogenesis of an epithelial tube, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005634 nucleus	IDA PMID:10206645 A presenilin-1-dependent gamma-secretase-like protease media...	ACCEPT	Summary: The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription. Reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007409 axonogenesis	IMP PMID:16120638 Notch signaling coordinates the patterning of striatal compa...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in axonogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030900 forebrain development	IMP PMID:16120638 Notch signaling coordinates the patterning of striatal compa...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in forebrain development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030900 forebrain development	IGI PMID:16120638 Notch signaling coordinates the patterning of striatal compa...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in forebrain development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045665 negative regulation of neuron differentiation	IMP PMID:16120638 Notch signaling coordinates the patterning of striatal compa...	KEEP AS NON CORE	Summary: Notch1 is involved in negative regulation of neuron differentiation via Notch-mediated lateral inhibition, a canonical function in the neuron-glia binary fate decision. Reason: Notch1-mediated effects on neuron differentiation are well-supported developmental outputs, but they are tissue-context consequences of the core juxtacrine receptor/NICD transcription mechanism rather than the core function itself. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0048663 neuron fate commitment	IGI PMID:16120638 Notch signaling coordinates the patterning of striatal compa...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in neuron fate commitment, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:15902259 The Mesp2 transcription factor establishes segmental borders...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0001708 cell fate specification	IMP PMID:15068794 High commitment of embryonic keratinocytes to terminal diffe...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in cell fate specification, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007409 axonogenesis	IDA PMID:15598981 Targeted deletion of numb and numblike in sensory neurons re...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in axonogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030154 cell differentiation	IMP PMID:12186854 Notch1 control of oligodendrocyte differentiation in the spi...	ACCEPT	Summary: Notch1 is a master regulator of cell-fate determination and differentiation across multiple tissue contexts. Reason: Cell differentiation regulation is a core biological role of Notch1 signaling. UniProt states Notch1 affects implementation of differentiation, proliferation and apoptotic programs. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030216 keratinocyte differentiation	IMP PMID:15068794 High commitment of embryonic keratinocytes to terminal diffe...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in keratinocyte differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0003682 chromatin binding	IDA PMID:15689374 RBPjkappa-dependent Notch function regulates Gata2 and is es...	ACCEPT	Summary: NICD associates with chromatin as part of the transcription activation complex with RBPJ. Reason: NICD binds to chromatin at target gene promoters as part of the RBPJ-MAML transcription complex. This is part of the core transcriptional mechanism. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0006357 regulation of transcription by RNA polymerase II	IGI PMID:15689374 RBPjkappa-dependent Notch function regulates Gata2 and is es...	KEEP AS NON CORE	Summary: Notch1 annotation to regulation of transcription by RNA polymerase II. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030324 lung development	IMP PMID:15064243 Functional diversity of notch family genes in fetal lung dev...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in lung development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045596 negative regulation of cell differentiation	IMP PMID:15064243 Functional diversity of notch family genes in fetal lung dev...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in negative regulation of cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0008284 positive regulation of cell population proliferation	IGI PMID:15509736 Fibroblast growth factor receptor signaling promotes radial ...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of cell population proliferation. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:12783854 Periodic repression by the bHLH factor Hes7 is an essential ...	KEEP AS NON CORE	Summary: Notch1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0048103 somatic stem cell division	IGI PMID:15509736 Fibroblast growth factor receptor signaling promotes radial ...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in somatic stem cell division, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0008544 epidermis development	IGI PMID:15525534 gamma-secretase functions through Notch signaling to maintai...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in epidermis development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0031069 hair follicle morphogenesis	IMP PMID:15525534 gamma-secretase functions through Notch signaling to maintai...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in hair follicle morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0043065 positive regulation of apoptotic process	IDA PMID:15081359 Notch activation induces apoptosis in neural progenitor cell...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in positive regulation of apoptotic process, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0001837 epithelial to mesenchymal transition	IMP PMID:14701881 Notch promotes epithelial-mesenchymal transition during card...	KEEP AS NON CORE	Summary: Notch1 promotes epithelial to mesenchymal transition. Reason: EMT regulation - context-dependent function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007492 endoderm development	IMP PMID:14657333 Notch signaling controls multiple steps of pancreatic differ...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in endoderm development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0030154 cell differentiation	IMP PMID:14657333 Notch signaling controls multiple steps of pancreatic differ...	ACCEPT	Summary: Notch1 is a master regulator of cell-fate determination and differentiation across multiple tissue contexts. Reason: Cell differentiation regulation is a core biological role of Notch1 signaling. UniProt states Notch1 affects implementation of differentiation, proliferation and apoptotic programs. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005886 plasma membrane	IC PMID:10551863 Mouse jagged1 physically interacts with notch2 and other not...	ACCEPT	Summary: Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007219 Notch signaling pathway	IC PMID:10551863 Mouse jagged1 physically interacts with notch2 and other not...	ACCEPT	Summary: Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex. Reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x). Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0048103 somatic stem cell division	IDA PMID:12717450 A role for Wnt signalling in self-renewal of haematopoietic ...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in somatic stem cell division, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007368 determination of left/right symmetry	IMP PMID:12730124 Notch signaling regulates left-right asymmetry determination...	KEEP AS NON CORE	Summary: Notch1 annotation to determination of left/right symmetry. Reason: Transferred annotation - context-specific function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0005515 protein binding	IPI PMID:10551863 Mouse jagged1 physically interacts with notch2 and other not...	REMOVE	Summary: The protein binding annotation records a physical interaction but is too generic to describe Notch1 function. Reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]
GO:0007386 compartment pattern specification	IMP PMID:12001066 Segmentation defects of Notch pathway mutants and absence of...	KEEP AS NON CORE	Summary: Notch1 has evidence for involvement in compartment pattern specification, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism. Reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function. Supporting Evidence: file:mouse/Notch1/Notch1-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.]

Core Functions

Notch1 functions as a transmembrane signaling receptor at the plasma membrane, responding to membrane-bound DLL/Jagged-family ligands on neighboring cells and transducing cell-cell contact signals through regulated intramembrane proteolysis.

Molecular Function:

transmembrane signaling receptor activity

Directly Involved In:

Notch signaling pathway cell differentiation

Cellular Locations:

plasma membrane cell surface

Supporting Evidence:

file:mouse/Notch1/Notch1-deep-research-falcon.md
[Falcon synthesis describes Notch1 as a mechanosensitive juxtacrine receptor activated by ligand-dependent cleavage.]

The cleaved Notch1 intracellular domain (NICD) functions as a transcriptional coactivator in the nucleus by binding CSL/RBPJ and recruiting MAML to activate canonical Notch target genes such as Hes and Hey family members.

Molecular Function:

transcription coactivator activity

Directly Involved In:

positive regulation of DNA-templated transcription positive regulation of transcription of Notch receptor target

Cellular Locations:

nucleus

In Complex:

MAML1-RBP-Jkappa- ICN1 complex

Supporting Evidence:

file:mouse/Notch1/Notch1-deep-research-falcon.md
[Falcon synthesis describes NICD nuclear entry and CSL/RBPJ-MAML target gene activation.]

Notch1 EGF-like repeats bind calcium ions, which supports receptor folding, stability, and ligand-binding competence.

Molecular Function:

calcium ion binding

Cellular Locations:

plasma membrane

Supporting Evidence:

file:mouse/Notch1/Notch1-deep-research-falcon.md
[Falcon synthesis identifies Notch1 as an EGF-repeat transmembrane receptor with ligand-binding extracellular modules.]

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000096

Automated transfer of experimentally-verified manual GO annotation data to mouse-rat orthologs

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000119

Automated transfer of experimentally-verified manual GO annotation data to mouse-human orthologs

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10205173

Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation.

PMID:10206645

A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.

PMID:10551863

Mouse jagged1 physically interacts with notch2 and other notch receptors. Assessment by quantitative methods.

PMID:10958687

Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2.

PMID:11076679

Oscillating expression of c-Hey2 in the presomitic mesoderm suggests that the segmentation clock may use combinatorial signaling through multiple interacting bHLH factors.

PMID:12001066

Segmentation defects of Notch pathway mutants and absence of a synergistic phenotype in lunatic fringe/radical fringe double mutant mice.

PMID:12032823

Overexpression of the Notch target genes Hes in vivo induces lymphoid and myeloid alterations.

PMID:12050162

The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway.

PMID:12186854

Notch1 control of oligodendrocyte differentiation in the spinal cord.

PMID:12666205

Hes1 but not Hes5 regulates an astrocyte versus oligodendrocyte fate choice in glial restricted precursors.

PMID:12717450

A role for Wnt signalling in self-renewal of haematopoietic stem cells.

PMID:12730124

Notch signaling regulates left-right asymmetry determination by inducing Nodal expression.

PMID:12783854

Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock.

PMID:12794108

Notch-regulated ankyrin-repeat protein inhibits Notch1 signaling: multiple Notch1 signaling pathways involved in T cell development.

PMID:14657333

Notch signaling controls multiple steps of pancreatic differentiation.

PMID:14701881

Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation.

PMID:15064243

Functional diversity of notch family genes in fetal lung development.

PMID:15068794

High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism.

PMID:15081359

Notch activation induces apoptosis in neural progenitor cells through a p53-dependent pathway.

PMID:15107403

The Notch target genes Hey1 and Hey2 are required for embryonic vascular development.

PMID:15156153

Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling.

PMID:15226394

Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors.

PMID:15509736

Fibroblast growth factor receptor signaling promotes radial glial identity and interacts with Notch1 signaling in telencephalic progenitors.

PMID:15525534

gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis.

PMID:15574878

Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1.

PMID:15598981

Targeted deletion of numb and numblike in sensory neurons reveals their essential functions in axon arborization.

PMID:15689374

RBPjkappa-dependent Notch function regulates Gata2 and is essential for the formation of intra-embryonic hematopoietic cells.

PMID:15809373

Essential role of endothelial Notch1 in angiogenesis.

PMID:15821257

Segmental expression of Notch and Hairy genes in nephrogenesis.

PMID:15902259

The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity.

PMID:15965470

DNER acts as a neuron-specific Notch ligand during Bergmann glial development.

PMID:15978571

Notch1 is essential for postnatal hair follicle development and homeostasis.

PMID:16025100

Mutations in NOTCH1 cause aortic valve disease.

PMID:16107537

Direct regulation of intestinal fate by Notch.

PMID:16120638

Notch signaling coordinates the patterning of striatal compartments.

PMID:16145673

Fjx1: a notch-inducible secreted ligand with specific binding sites in developing mouse embryos and adult brain.

PMID:16169548

Notch1 and 2 cooperate in limb ectoderm to receive an early Jagged2 signal regulating interdigital apoptosis.

PMID:16245338

Notch1 signals through Jagged2 to regulate apoptosis in the apical ectodermal ridge of the developing limb bud.

PMID:16324690

BMP7 inhibits branching morphogenesis in the prostate gland and interferes with Notch signaling.

PMID:16360140

Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation.

PMID:16452096

Notch 1 inhibits photoreceptor production in the developing mammalian retina.

PMID:16607638

Jag2-Notch1 signaling regulates oral epithelial differentiation and palate development.

PMID:16618808

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation.

PMID:17079689

Canonical notch signaling functions as a commitment switch in the epidermal lineage.

PMID:17210915

Baf60c is a nuclear Notch signaling component required for the establishment of left-right asymmetry.

PMID:17303760

Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition.

PMID:17336907

Notch signaling is essential for ventricular chamber development.

PMID:17573339

Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor.

PMID:17658278

Notch directly regulates Gata3 expression during T helper 2 cell differentiation.

PMID:17658279

Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch.

PMID:17685488

Monitoring Notch1 activity in development: evidence for a feedback regulatory loop.

PMID:18299578

Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways.

PMID:18430783

Zfp64 participates in Notch signaling and regulates differentiation in mesenchymal cells.

PMID:18676613

The intracellular region of Notch ligands Dll1 and Dll3 regulates their trafficking and signaling activity.

PMID:18952909

Artery and vein size is balanced by Notch and ephrin B2/EphB4 during angiogenesis.

PMID:19154718

Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti.

PMID:19245366

MYPT1, the targeting subunit of smooth-muscle myosin phosphatase, is a substrate for the asparaginyl hydroxylase factor inhibiting hypoxia-inducible factor (FIH).

PMID:19251639

Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine.

PMID:19620969

A regulatory pathway involving Notch1/beta-catenin/Isl1 determines cardiac progenitor cell fate.

PMID:19695258

Notch1 represses osteogenic pathways in aortic valve cells.

PMID:20007915

Distinct roles for cell-autonomous Notch signaling in cardiomyocytes of the embryonic and adult heart.

PMID:20547764

ZFP423 coordinates Notch and bone morphogenetic protein signaling, selectively up-regulating Hes5 gene expression.

PMID:20890042

Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation.

PMID:21102556

RITA, a novel modulator of Notch signalling, acts via nuclear export of RBP-J.

PMID:21156799

Intracellular pathogen sensor NOD2 programs macrophages to trigger Notch1 activation.

PMID:21191019

A protein (ORF2) encoded by the latency-related gene of bovine herpesvirus 1 interacts with Notch1 and Notch3.

PMID:21266778

Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways.

PMID:21311046

Differential Notch signaling in the epicardium is required for cardiac inflow development and coronary vessel morphogenesis.

PMID:21315255

Activity-induced Notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks.

PMID:21419176

The EGF-like proteins DLK1 and DLK2 function as inhibitory non-canonical ligands of NOTCH1 receptor that modulate each other's activities.

PMID:21493891

Diet-induced aortic valve disease in mice haploinsufficient for the Notch pathway effector RBPJK/CSL.

PMID:21985982

Delta-like 1-Lysine613 regulates notch signaling.

PMID:22110751

Inhibitory role of Notch1 in calcific aortic valve disease.

PMID:22147266

Analysis of early C2C12 myogenesis identifies stably and differentially expressed transcriptional regulators whose knock-down inhibits myoblast differentiation.

PMID:22258620

Pten coordinates retinal neurogenesis by regulating Notch signalling.

PMID:23160044

BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets.

PMID:23284756

Ascl1 (Mash1) knockout perturbs differentiation of nonneuronal cells in olfactory epithelium.

PMID:23382219

Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.

PMID:23583836

Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease.

PMID:24667410

Notch4 reveals a novel mechanism regulating Notch signal transduction.

PMID:24715457

Cadherin-based adhesions in the apical endfoot are required for active Notch signaling to control neurogenesis in vertebrates.

PMID:25038826

Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity.

PMID:25535395

Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway.

PMID:26491108

Notch-Tnf signalling is required for development and homeostasis of arterial valves.

PMID:26635527

Notch1 Regulates Hippocampal Plasticity Through Interaction with the Reelin Pathway, Glutamatergic Transmission and CREB Signaling.

PMID:27107132

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract.

PMID:27719760

BLOS2 negatively regulates Notch signaling during neural and hematopoietic stem and progenitor cell development.

PMID:28089369

Deciphering the Fringe-Mediated Notch Code: Identification of Activating and Inhibiting Sites Allowing Discrimination between Ligands.

PMID:28498977

Consequences of MEGF10 deficiency on myoblast function and Notch1 interactions.

PMID:28561022

IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression.

PMID:38891776

Pin1 Downregulation Is Involved in Excess Retinoic Acid-Induced Failure of Neural Tube Closure.

PMID:7789282

Notch1 is required for the coordinate segmentation of somites.

PMID:8749394

Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H).

PMID:9102301

Conservation of the Notch signalling pathway in mammalian neurogenesis.

PMID:9111338

RBP-L, a transcription factor related to RBP-Jkappa.

PMID:9315665

Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor.

Reactome:R-MMU-2023158

Glycosylation of Pre-Notch by Fringe

Reactome:R-MMU-2023179

Glucosylation of Pre-Notch by Poglut1

Reactome:R-MMU-2032750

Sel1l negatively regulates Pre-Notch exit from endoplasmic reticulum

Reactome:R-MMU-2053938

Dll4 binds Notch1

Reactome:R-MMU-2053963

Notch1 binds Jag1

Reactome:R-MMU-2066712

Dner binds Notch1

Reactome:R-MMU-2067638

Gamma secretase cleaves Dner:Notch1 complex

Reactome:R-MMU-2071906

Notch1 binds Dlk1

Reactome:R-MMU-2077477

Numb recruits Itch to Notch1

Reactome:R-MMU-2077479

Itch ubiquitinates Notch

Reactome:R-MMU-209285

The transmembrane complex Murine gamma-secretase cleaves Murine NEXT at the S3 site leaving NTM and releasing NICD into the cytoplasm

Reactome:R-MMU-4396387

mNOTCH1 coactivator complex bind promoters of Hey genes

Reactome:R-MMU-9667655

Nbea binds nicd1

Reactome:R-MMU-9793875

Dll3 binds Notch1

Reactome:R-MMU-9824206

Lef1:Ctnnb1, Nicd (Notch), and Tbx6 bind the Hes7 gene in presomitic mesoderm

Reactome:R-MMU-9824230

Hes7 binds the Lfng gene

Reactome:R-MMU-9824231

Rbpj:Nicd and Msgn1 bind the Lfng gene

Reactome:R-MMU-9824249

Expression of Notch1 in presomitic mesoderm

Reactome:R-MMU-9824278

Hes7 binds the Hes7 gene

Reactome:R-NUL-1986584

Fucosylation of Pre-Notch by POFUT1

Reactome:R-NUL-2063915

ADAM17 cleaves Notch1 at S2

Reactome:R-NUL-2064853

FBXW7 binds phosphorylated NICD1

Reactome:R-NUL-2064883

FBXW7 mediates ubiquitination of phosphorylated NICD1

Reactome:R-NUL-2065560

mNICD1 binds HIF1A

Reactome:R-NUL-2065902

Gamma secretase complex cleaves Cntn1-actived Notch1

Reactome:R-NUL-209162

Murine ADAM10 cleaves Notch at the S2 site producing transmembrane spanning NEXT and ligand-bound NECD

Reactome:R-NUL-4396363

mNICD1 Chimeric Enhancer Complex binds Hes1 promoter

file:mouse/Notch1/Notch1-deep-research-falcon.md

Falcon deep research report on mouse Notch1 function

file:interpro/panther/PTHR45836/PTHR45836-metadata.yaml

PANTHER PTHR45836 Notch and Slit guidance protein family metadata

file:interpro/panther/PTHR45836/PTHR45836-entries.csv

Reviewed protein members for PANTHER PTHR45836

📚 Additional Documentation

Deep Research Bioreason

(Notch1-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:24 AM

Organism: Mus musculus

Sequence:

MPRLLTPLLCLTLLPALAARGLRCSQPSGTCLNGGRCEVANGTEACVCSGAFVGQRCQDSNPCLSTPCKNAGTCHVVDHGGTVDYACSCPLGFSGPLCLTPLDNACLANPCRNGGTCDLLTLTEYKCRCPPGWSGKSCQQADPCASNPCANGGQCLPFESSYICRCPPGFHGPTCRQDVNECSQNPGLCRHGGTCHNEIGSYRCACRATHTGPHCELPYVPCSPSPCQNGGTCRPTGDTTHECACLPGFAGQNCEENVDDCPGNNCKNGGACVDGVNTYNCRCPPEWTGQYCTEDVDECQLMPNACQNGGTCHNTHGGYNCVCVNGWTGEDCSENIDDCASAACFQGATCHDRVASFYCECPHGRTGLLCHLNDACISNPCNEGSNCDTNPVNGKAICTCPSGYTGPACSQDVDECALGANPCEHAGKCLNTLGSFECQCLQGYTGPRCEIDVNECISNPCQNDATCLDQIGEFQCICMPGYEGVYCEINTDECASSPCLHNGHCMDKINEFQCQCPKGFNGHLCQYDVDECASTPCKNGAKCLDGPNTYTCVCTEGYTGTHCEVDIDECDPDPCHYGSCKDGVATFTCLCQPGYTGHHCETNINECHSQPCRHGGTCQDRDNSYLCLCLKGTTGPNCEINLDDCASNPCDSGTCLDKIDGYECACEPGYTGSMCNVNIDECAGSPCHNGGTCEDGIAGFTCRCPEGYHDPTCLSEVNECNSNPCIHGACRDGLNGYKCDCAPGWSGTNCDINNNECESNPCVNGGTCKDMTSGYVCTCREGFSGPNCQTNINECASNPCLNQGTCIDDVAGYKCNCPLPYTGATCEVVLAPCATSPCKNSGVCKESEDYESFSCVCPTGWQGQTCEVDINECVKSPCRHGASCQNTNGSYRCLCQAGYTGRNCESDIDDCRPNPCHNGGSCTDGINTAFCDCLPGFQGAFCEEDINECASNPCQNGANCTDCVDSYTCTCPVGFNGIHCENNTPDCTESSCFNGGTCVDGINSFTCLCPPGFTGSYCQYDVNECDSRPCLHGGTCQDSYGTYKCTCPQGYTGLNCQNLVRWCDSAPCKNGGRCWQTNTQYHCECRSGWTGVNCDVLSVSCEVAAQKRGIDVTLLCQHGGLCVDEGDKHYCHCQAGYTGSYCEDEVDECSPNPCQNGATCTDYLGGFSCKCVAGYHGSNCSEEINECLSQPCQNGGTCIDLTNSYKCSCPRGTQGVHCEINVDDCHPPLDPASRSPKCFNNGTCVDQVGGYTCTCPPGFVGERCEGDVNECLSNPCDPRGTQNCVQRVNDFHCECRAGHTGRRCESVINGCRGKPCKNGGVCAVASNTARGFICRCPAGFEGATCENDARTCGSLRCLNGGTCISGPRSPTCLCLGSFTGPECQFPASSPCVGSNPCYNQGTCEPTSENPFYRCLCPAKFNGLLCHILDYSFTGGAGRDIPPPQIEEACELPECQVDAGNKVCNLQCNNHACGWDGGDCSLNFNDPWKNCTQSLQCWKYFSDGHCDSQCNSAGCLFDGFDCQLTEGQCNPLYDQYCKDHFSDGHCDQGCNSAECEWDGLDCAEHVPERLAAGTLVLVVLLPPDQLRNNSFHFLRELSHVLHTNVVFKRDAQGQQMIFPYYGHEEELRKHPIKRSTVGWATSSLLPGTSGGRQRRELDPMDIRGSIVYLEIDNRQCVQSSSQCFQSATDVAAFLGALASLGSLNIPYKIEAVKSEPVEPPLPSQLHLMYVAAAAFVLLFFVGCGVLLSRKRRRQHGQLWFPEGFKVSEASKKKRREPLGEDSVGLKPLKNASDGALMDDNQNEWGDEDLETKKFRFEEPVVLPDLSDQTDHRQWTQQHLDAADLRMSAMAPTPPQGEVDADCMDVNVRGPDGFTPLMIASCSGGGLETGNSEEEEDAPAVISDFIYQGASLHNQTDRTGETALHLAARYSRSDAAKRLLEASADANIQDNMGRTPLHAAVSADAQGVFQILLRNRATDLDARMHDGTTPLILAARLAVEGM

Thinking Trace

I begin with the InterPro architecture. A broad family signature, IPR008297 (Notch family, residues 5–2000), blankets essentially the entire polypeptide, immediately placing the protein within the Notch receptor lineage. The N-terminal half is densely packed with extracellular EGF modules: IPR000742 (EGF-like domain, residues 20–1426), IPR001881 (EGF-like calcium-binding domain, residues 59–1384), IPR018097 (EGF-like calcium-binding conserved site, residues 178–1253), and IPR049883 (NOTCH1, EGF-like calcium-binding domain, residues 178–900). These repeated EGF repeats and their Ca2+-binding motifs generate a rigid, cysteine-rich scaffold that enforces precise intermolecular contacts and mechanosensing at the cell surface. This extracellular region is further supported by IPR009030 (Growth factor receptor cysteine-rich domain superfamily, residues 288–1311), emphasizing a disulfide-stabilized receptor fold, and by IPR000152 (EGF-type aspartate/asparagine hydroxylation site, residues 195–1255) and IPR013032 (EGF-like conserved site, residues 344–1374), which together indicate extensive post-translational hydroxylation and glycosylation typical of secreted or surface-exposed EGF arrays. This extracellular EGF architecture causes high-affinity, Ca2+-tunable binding and force-dependent activation characteristic of Notch receptors.

Proceeding into the intracellular signaling core, a series of Notch-specific modules appears: IPR022362 (Neurogenic locus notch homolog protein 1 family, residues 1426–1714) leads into IPR000800 (Notch domain, residues 1442–1571), IPR035993 (Notch-like domain superfamily, residues 1448–1561), IPR010660 (Notch, NOD domain, residues 1566–1622), and IPR011656 (Notch, NODP domain, residues 1660–1722). This ordered block encodes the canonical heterodimerization and negative regulatory apparatus of Notch receptors: the NOD/NODP cassette forms the negative regulatory region that clamps the receptor’s intracellular tail until activating endocytosis and mechanical tension unlock it. Downstream, IPR036770 (Ankyrin repeat-containing domain superfamily, residues 1858–2000) and IPR002110 (Ankyrin repeat, residues 1870–1980) specify a C-terminal ankyrin-repeat platform that binds transcriptional co-regulators. The combined evidence—extracellular EGF arrays, followed by the NOD/NODP switch and a C-terminal ankyrin scaffold—defines a single-pass type I receptor that signals by proteolytic activation and intracellular complex assembly.

From this architecture, the molecular function resolves as follows. The extracellular EGF array and calcium-binding sites enforce ligand-gated activation and support protein-protein interactions at the surface; the intracellular ankyrin repeats and the activated signaling core drive assembly of transcriptional effector complexes. This causally establishes protein binding (GO:0005515) as the operative activity: the receptor binds extracellular ligands and intracellular partners to translate a surface cue into transcriptional control.

The biological process follows from this signaling logic. Notch receptors govern binary fate decisions by inducing gene expression programs that restrain or promote differentiation. The EGF-driven activation and ankyrin-mediated transcriptional assembly together enforce control of lineage bifurcation and timing, aligning with cell fate determination (GO:0001708). This process-level inference arises directly from the coupling of an extracellular ligand-gated module to an intracellular transcriptional hub.

Cellular location is dictated by the single-pass type I topology and the extracellular EGF region. Such receptors are synthesized into the secretory pathway and displayed at the cell surface, where they function as membrane-bound signal transducers. This places the protein at the plasma membrane/cell surface and classifies it as an integral component of membrane, matching a single-pass type I membrane protein.

Mechanistically, the extracellular EGF platform binds Delta/Serrate/Jagged-type ligands on neighboring cells; endocytosis and Ca2+-stabilized EGF architecture transmit mechanical force that unlocks the NOD/NODP switch, triggering intramembrane proteolysis and liberation of the intracellular domain. The released intracellular fragment then engages the ankyrin-repeat platform to recruit CSL/RBPJ transcription complexes and coactivators, thereby rewiring gene expression to bias cell fate. Likely interaction partners include membrane ligands and extracellular modulators that deliver activation cues, as well as intracellular DNA-binding and co-regulatory assemblies that implement the transcriptional output.

Functional Summary

A single-pass cell-surface receptor that uses a long calcium-stabilized EGF repeat array to sense extracellular cues and trigger intramembrane signaling. Upon ligand engagement and endocytic activation, a built-in regulatory switch releases the intracellular tail, which then assembles transcriptional effector complexes via ankyrin repeats to reprogram gene expression. This signaling cascade governs binary fate decisions and timing of differentiation by coupling extracellular recognition to intracellular transcriptional control at the plasma membrane.

UniProt Summary

Functions as a receptor for several membrane-bound ligands that are presented on the surface of adjacent cells. Activates transcription factors that are involved in lineage specification. May play a role in cell-fate determination (By similarity).

InterPro Domains

Notch (IPR008297, family) — residues 5-2000
EGF-like domain (IPR000742, domain) — residues 20-1426
EGF-like calcium-binding domain (IPR001881, domain) — residues 59-1384
EGF-like calcium-binding, conserved site (IPR018097, conserved_site) — residues 178-1253
NOTCH1, EGF-like calcium-binding domain (IPR049883, domain) — residues 178-900
EGF-type aspartate/asparagine hydroxylation site (IPR000152, ptm) — residues 195-1255
Growth factor receptor cysteine-rich domain superfamily (IPR009030, homologous_superfamily) — residues 288-1311
EGF-like, conserved site (IPR013032, conserved_site) — residues 344-1374
Neurogenic locus notch homolog protein 1 (IPR022362, family) — residues 1426-1714
Notch domain (IPR000800, domain) — residues 1442-1571
Notch-like domain superfamily (IPR035993, homologous_superfamily) — residues 1448-1561
Notch, NOD domain (IPR010660, domain) — residues 1566-1622
Notch, NODP domain (IPR011656, domain) — residues 1660-1722
Ankyrin repeat-containing domain superfamily (IPR036770, homologous_superfamily) — residues 1858-2000
Ankyrin repeat (IPR002110, repeat) — residues 1870-1980

GO Terms

Molecular Function: molecular_function (GO:0003674), molecular function regulator activity (GO:0098772), binding (GO:0005488), transcription regulator activity (GO:0140110), enzyme regulator activity (GO:0030234), molecular function activator activity (GO:0140677), heterocyclic compound binding (GO:1901363), chromatin binding (GO:0003682), organic cyclic compound binding (GO:0097159), transcription coregulator activity (GO:0003712), protein binding (GO:0005515), molecular function inhibitor activity (GO:0140678), nucleic acid binding (GO:0003676), signaling receptor binding (GO:0005102), chromatin DNA binding (GO:0031490), enzyme binding (GO:0019899), enzyme inhibitor activity (GO:0004857), transcription coactivator activity (GO:0003713), Notch binding (GO:0005112), DNA binding (GO:0003677)

Biological Process: biological_process (GO:0008150), biological regulation (GO:0065007), response to stimulus (GO:0050896), reproductive process (GO:0022414), regulation of biological process (GO:0050789), reproduction (GO:0000003), multicellular organismal process (GO:0032501), metabolic process (GO:0008152), homeostatic process (GO:0042592), immune system process (GO:0002376), localization (GO:0051179), signaling (GO:0023052), growth (GO:0040007), negative regulation of biological process (GO:0048519), positive regulation of biological process (GO:0048518), developmental process (GO:0032502), cellular process (GO:0009987), anatomical structure development (GO:0048856), negative regulation of signaling (GO:0023057), cell division (GO:0051301), developmental process involved in reproduction (GO:0003006), anatomical structure formation involved in morphogenesis (GO:0048646), multicellular organismal-level homeostasis (GO:0048871), regulation of response to stimulus (GO:0048583), negative regulation of cellular process (GO:0048523), biosynthetic process (GO:0009058), positive regulation of viral process (GO:0048524), establishment of localization (GO:0051234), catabolic process (GO:0009056), macromolecule localization (GO:0033036), developmental growth (GO:0048589), cell population proliferation (GO:0008283), nitrogen compound metabolic process (GO:0006807), negative regulation of multicellular organismal process (GO:0051241), cell death (GO:0008219), positive regulation of locomotion (GO:0040017), regulation of signaling (GO:0023051), negative regulation of developmental process (GO:0051093), signal transduction (GO:0007165), negative regulation of transport (GO:0051051), regulation of viral process (GO:0050792), primary metabolic process (GO:0044238), morphogenesis of a branching structure (GO:0001763), positive regulation of developmental process (GO:0051094), negative regulation of response to stimulus (GO:0048585), regulation of growth (GO:0040008), cellular localization (GO:0051641), immune response (GO:0006955), positive regulation of multicellular organismal process (GO:0051240), molting cycle (GO:0042303), pattern specification process (GO:0007389), cellular component organization or biogenesis (GO:0071840), regulation of multicellular organismal process (GO:0051239), negative regulation of metabolic process (GO:0009892), regulation of cellular process (GO:0050794), cellular response to stimulus (GO:0051716), regulation of locomotion (GO:0040012), cellular developmental process (GO:0048869), response to abiotic stimulus (GO:0009628), organ growth (GO:0035265), positive regulation of response to stimulus (GO:0048584), regulation of metabolic process (GO:0019222), molting cycle process (GO:0022404), regulation of molecular function (GO:0065009), export from cell (GO:0140352), cell communication (GO:0007154), positive regulation of cellular process (GO:0048522), anatomical structure morphogenesis (GO:0009653), cell motility (GO:0048870), response to chemical (GO:0042221), regulation of reproductive process (GO:2000241), positive regulation of growth (GO:0045927), regulation of developmental process (GO:0050793), positive regulation of signaling (GO:0023056), multicellular organism development (GO:0007275), regulation of localization (GO:0032879), organic substance metabolic process (GO:0071704), cellular metabolic process (GO:0044237), positive regulation of metabolic process (GO:0009893), response to stress (GO:0006950), cellular component morphogenesis (GO:0032989), negative regulation of cellular component organization (GO:0051129), regulation of cell motility (GO:2000145), regulation of system process (GO:0044057), animal organ development (GO:0048513), neural retina development (GO:0003407), regulation of vesicle-mediated transport (GO:0060627), positive regulation of apoptotic process involved in development (GO:1904747), negative regulation of cellular response to growth factor stimulus (GO:0090288), retina development in camera-type eye (GO:0060041), negative regulation of secretion (GO:0051048), regulation of development, heterochronic (GO:0040034), cardiac septum morphogenesis (GO:0060411), regulation of anatomical structure morphogenesis (GO:0022603), secretion by cell (GO:0032940), nephron development (GO:0072006), trabecula morphogenesis (GO:0061383), negative regulation of muscle hypertrophy (GO:0014741), positive regulation of epidermis development (GO:0045684), positive regulation of nitrogen compound metabolic process (GO:0051173), positive regulation of cell differentiation (GO:0045597), appendage development (GO:0048736), organic substance biosynthetic process (GO:1901576), negative regulation of cell population proliferation (GO:0008285), protein metabolic process (GO:0019538), specification of symmetry (GO:0009799), cellular biosynthetic process (GO:0044249), response to oxygen-containing compound (GO:1901700), prostate gland epithelium morphogenesis (GO:0060740), macromolecule metabolic process (GO:0043170), positive regulation of cell motility (GO:2000147), positive regulation of biosynthetic process (GO:0009891), homeostasis of number of cells (GO:0048872), endocardial cushion formation (GO:0003272), muscle structure development (GO:0061061), regulation of cell population proliferation (GO:0042127), regulation of cell death (GO:0010941), regionalization (GO:0003002), response to nitrogen compound (GO:1901698), negative regulation of cell differentiation (GO:0045596), transport (GO:0006810), humoral immune response (GO:0006959), positive regulation of cell communication (GO:0010647), regulation of cellular metabolic process (GO:0031323), hair cycle process (GO:0022405), regulation of primary metabolic process (GO:0080090), negative regulation of signal transduction (GO:0009968), response to hypoxia (GO:0001666), regulation of viral genome replication (GO:0045069), negative regulation of cell death (GO:0060548), cell differentiation (GO:0030154), negative regulation of nervous system development (GO:0051961), system development (GO:0048731), response to oxygen levels (GO:0070482), cardiac septum development (GO:0003279), regulation of cell adhesion (GO:0030155), regulation of organ growth (GO:0046620), heart growth (GO:0060419), tube development (GO:0035295), cell morphogenesis (GO:0000902), animal organ morphogenesis (GO:0009887), cell surface receptor signaling pathway (GO:0007166), regulation of cellular component organization (GO:0051128), negative regulation of biomineral tissue development (GO:0070168), regulation of ossification (GO:0030278), positive regulation of cell population proliferation (GO:0008284), tube morphogenesis (GO:0035239), positive regulation of developmental growth (GO:0048639), negative regulation of cell communication (GO:0010648), apoptotic process involved in development (GO:1902742), axis specification (GO:0009798), retina morphogenesis in camera-type eye (GO:0060042), hair follicle morphogenesis (GO:0031069), morphogenesis of a branching epithelium (GO:0061138), positive regulation of organ growth (GO:0046622), cardiac chamber development (GO:0003205), negative regulation of cellular metabolic process (GO:0031324), cell fate commitment (GO:0045165), embryonic morphogenesis (GO:0048598), cellular response to chemical stimulus (GO:0070887), glomerulus development (GO:0032835), tissue homeostasis (GO:0001894), stem cell division (GO:0017145), hair cycle (GO:0042633), regulation of cold-induced thermogenesis (GO:0120161), developmental growth involved in morphogenesis (GO:0060560), negative regulation of photoreceptor cell differentiation (GO:0046533), regulation of signal transduction (GO:0009966), foregut morphogenesis (GO:0007440), regulation of macromolecule metabolic process (GO:0060255), reproductive structure development (GO:0048608), cellular aromatic compound metabolic process (GO:0006725), regulation of muscle adaptation (GO:0043502), positive regulation of epithelial to mesenchymal transition (GO:0010718), establishment of protein localization (GO:0045184), regulation of cellular component biogenesis (GO:0044087), regulation of apoptotic process involved in development (GO:1904748), intracellular transport (GO:0046907), negative regulation of macromolecule metabolic process (GO:0010605), muscle cell proliferation (GO:0033002), embryo development (GO:0009790), regulation of catalytic activity (GO:0050790), negative regulation of nitrogen compound metabolic process (GO:0051172), regulation of epidermis development (GO:0045682), positive regulation of macromolecule metabolic process (GO:0010604), blood vessel development (GO:0001568), heterocycle metabolic process (GO:0046483), negative regulation of molecular function (GO:0044092), establishment of localization in cell (GO:0051649), appendage morphogenesis (GO:0035107), cellular nitrogen compound metabolic process (GO:0034641), apoptotic process involved in morphogenesis (GO:0060561), angiogenesis (GO:0001525), regulation of multicellular organismal development (GO:2000026), regulation of viral transcription (GO:0046782), positive regulation of cellular metabolic process (GO:0031325), cellular response to stress (GO:0033554), epithelial cell proliferation (GO:0050673), cellular macromolecule localization (GO:0070727), negative regulation of biosynthetic process (GO:0009890), regulation of cellular response to growth factor stimulus (GO:0090287), positive regulation of cell death (GO:0010942), tissue morphogenesis (GO:0048729), programmed cell death (GO:0012501), adaptive immune response (GO:0002250), cell development (GO:0048468), prostate gland morphogenesis (GO:0060512), cardiac muscle tissue growth (GO:0055017), cell fate determination (GO:0001708), heart valve development (GO:0003170), negative regulation of ossification (GO:0030279), inflammatory response to antigenic stimulus (GO:0002437), organic cyclic compound metabolic process (GO:1901360), forebrain development (GO:0030900), hair follicle development (GO:0001942), regulation of nitrogen compound metabolic process (GO:0051171), regulation of cell differentiation (GO:0045595), cellular component organization (GO:0016043), inner ear development (GO:0048839), organic substance catabolic process (GO:1901575), positive regulation of nervous system development (GO:0051962), negative regulation of secretion by cell (GO:1903531), regulation of developmental growth (GO:0048638), endocardium development (GO:0003157), cell migration (GO:0016477), positive regulation of signal transduction (GO:0009967), regulation of secretion by cell (GO:1903530), positive regulation of viral genome replication (GO:0045070), regulation of transport (GO:0051049), organonitrogen compound metabolic process (GO:1901564), defense response (GO:0006952), response to organic substance (GO:0010033), anatomical structure homeostasis (GO:0060249), regulation of viral life cycle (GO:1903900), tissue development (GO:0009888), nucleobase-containing compound metabolic process (GO:0006139), head development (GO:0060322), regulation of cell communication (GO:0010646), regulation of biosynthetic process (GO:0009889), cardiac chamber morphogenesis (GO:0003206), heart valve morphogenesis (GO:0003179), negative regulation of cold-induced thermogenesis (GO:0120163), endoderm development (GO:0007492), regulation of hematopoietic progenitor cell differentiation (GO:1901532), nephron epithelium development (GO:0072009), cell projection organization (GO:0030030), regulation of Notch signaling pathway (GO:0008593), somatic stem cell division (GO:0048103), regulation of transmembrane receptor protein serine/threonine kinase signaling pathway (GO:0090092), positive regulation of cardiac muscle cell proliferation (GO:0060045), regulation of receptor signaling pathway via STAT (GO:1904892), regulation of epithelial cell proliferation (GO:0050678), semi-lunar valve development (GO:1905314), muscle cell differentiation (GO:0042692), embryonic heart tube development (GO:0035050), cell surface receptor signaling pathway involved in heart development (GO:0061311), circulatory system development (GO:0072359), response to decreased oxygen levels (GO:0036293), positive regulation of cell migration (GO:0030335), regulation of osteoblast differentiation (GO:0045667), cell projection morphogenesis (GO:0048858), pulmonary valve morphogenesis (GO:0003184), cytokine-mediated signaling pathway (GO:0019221), negative regulation of exocytosis (GO:0045920), ventricular septum development (GO:0003281), positive regulation of Notch signaling pathway (GO:0045747), regulation of cell proliferation involved in heart morphogenesis (GO:2000136), cellular response to organic substance (GO:0071310), establishment of protein localization to organelle (GO:0072594), cell migration involved in heart development (GO:0060973), positive regulation of epithelial cell differentiation (GO:0030858), limb morphogenesis (GO:0035108), regulation of muscle cell differentiation (GO:0051147), hepaticobiliary system development (GO:0061008), skeletal muscle cell differentiation (GO:0035914), Notch signaling pathway (GO:0007219), cardiac atrium morphogenesis (GO:0003209), positive regulation of macromolecule biosynthetic process (GO:0010557), apoptotic process (GO:0006915), adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains (GO:0002460), regulation of nucleobase-containing compound metabolic process (GO:0019219), epithelium development (GO:0060429), gland morphogenesis (GO:0022612), positive regulation of cellular biosynthetic process (GO:0031328), atrioventricular valve morphogenesis (GO:0003181), regulation of epithelial cell differentiation (GO:0030856), respiratory system development (GO:0060541), response to peptide (GO:1901652), regulation of programmed cell death (GO:0043067), protein catabolic process (GO:0030163), gland development (GO:0048732), cell differentiation involved in kidney development (GO:0061005), cardiac ventricle development (GO:0003231), morphogenesis of an epithelium (GO:0002009), positive regulation of neurogenesis (GO:0050769), skin development (GO:0043588), regulation of cell migration (GO:0030334), neuron development (GO:0048666), coronary vasculature development (GO:0060976), branching morphogenesis of an epithelial tube (GO:0048754), cardiac ventricle morphogenesis (GO:0003208), macromolecule catabolic process (GO:0009057), embryonic organ development (GO:0048568), cell morphogenesis involved in differentiation (GO:0000904), exocytosis (GO:0006887), renal tubule development (GO:0061326), nucleic acid metabolic process (GO:0090304), camera-type eye photoreceptor cell differentiation (GO:0060219), regulation of extracellular matrix organization (GO:1903053), negative regulation of cellular biosynthetic process (GO:0031327), negative regulation of Wnt signaling pathway (GO:0030178), mesenchymal cell differentiation (GO:0048762), negative regulation of cardiac muscle hypertrophy (GO:0010614), gene expression (GO:0010467), negative regulation of nucleobase-containing compound metabolic process (GO:0045934), regulation of cardiac muscle cell proliferation (GO:0060043), renal system development (GO:0072001), cardiac muscle cell proliferation (GO:0060038), reproductive system development (GO:0061458), negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway (GO:0090101), embryonic organ morphogenesis (GO:0048562), negative regulation of hematopoietic progenitor cell differentiation (GO:1901533), positive regulation of cell development (GO:0010720), urogenital system development (GO:0001655), positive regulation of gene expression (GO:0010628), muscle organ morphogenesis (GO:0048644), positive regulation of receptor signaling pathway via STAT (GO:1904894), positive regulation of nucleobase-containing compound metabolic process (GO:0045935), regulation of extracellular matrix assembly (GO:1901201), respiratory tube development (GO:0030323), response to organonitrogen compound (GO:0010243), positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway (GO:0090100), prostate gland development (GO:0030850), venous blood vessel development (GO:0060841), negative regulation of macromolecule biosynthetic process (GO:0010558), cardiac atrium development (GO:0003230), cardiocyte differentiation (GO:0035051), blood vessel endothelial cell differentiation (GO:0060837), regulation of epithelial to mesenchymal transition (GO:0010717), glomerulus vasculature development (GO:0072012), digestive tract development (GO:0048565), neuron differentiation (GO:0030182), cardiac cell development (GO:0055006), epithelial tube morphogenesis (GO:0060562), nitrogen compound transport (GO:0071705), embryonic digit morphogenesis (GO:0042733), regulation of macromolecule biosynthetic process (GO:0010556), cellular response to oxygen levels (GO:0071453), sensory system development (GO:0048880), vasculature development (GO:0001944), connective tissue development (GO:0061448), regulation of glial cell proliferation (GO:0060251), glial cell differentiation (GO:0010001), organic substance transport (GO:0071702), embryonic heart tube morphogenesis (GO:0003143), negative regulation of muscle cell differentiation (GO:0051148), regulation of gene expression (GO:0010468), regulation of cardiac muscle tissue growth (GO:0055021), striated muscle cell proliferation (GO:0014855), intracellular protein transport (GO:0006886), negative regulation of osteoblast differentiation (GO:0045668), epithelial cell development (GO:0002064), regulation of embryonic development (GO:0045995), heart trabecula morphogenesis (GO:0061384), epidermal cell fate specification (GO:0009957), sprouting angiogenesis (GO:0002040), heart development (GO:0007507), artery development (GO:0060840), cellular response to hypoxia (GO:0071456), positive regulation of heart growth (GO:0060421), atrioventricular valve development (GO:0003171), organonitrogen compound catabolic process (GO:1901565), epithelial cell fate commitment (GO:0072148), neuron fate commitment (GO:0048663), muscle cell development (GO:0055001), aromatic compound biosynthetic process (GO:0019438), regulation of cell development (GO:0060284), sensory organ development (GO:0007423), regulation of exocytosis (GO:0017157), secretion (GO:0046903), regulation of Wnt signaling pathway (GO:0030111), regulation of glial cell differentiation (GO:0045685), positive regulation of epithelial cell proliferation (GO:0050679), neurogenesis (GO:0022008), positive regulation of RNA metabolic process (GO:0051254), ventricular septum morphogenesis (GO:0060412), inflammatory response (GO:0006954), negative regulation of epithelial cell proliferation (GO:0050680), left/right pattern formation (GO:0060972), muscle tissue development (GO:0060537), regulation of stem cell proliferation (GO:0072091), regulation of cellular biosynthetic process (GO:0031326), regulation of cardiac muscle hypertrophy (GO:0010611), cellular nitrogen compound biosynthetic process (GO:0044271), embryonic appendage morphogenesis (GO:0035113), protein localization (GO:0008104), muscle organ development (GO:0007517), negative regulation of cell development (GO:0010721), embryo development ending in birth or egg hatching (GO:0009792), regulation of neuron differentiation (GO:0045664), macromolecule biosynthetic process (GO:0009059), organic cyclic compound biosynthetic process (GO:1901362), negative regulation of BMP signaling pathway (GO:0030514), digestive system development (GO:0055123), cell part morphogenesis (GO:0032990), sensory organ morphogenesis (GO:0090596), nuclear transport (GO:0051169), aortic valve morphogenesis (GO:0003180), regulation of BMP signaling pathway (GO:0030510), regulation of muscle system process (GO:0090257), regulation of epidermal cell differentiation (GO:0045604), brain development (GO:0007420), negative regulation of neurogenesis (GO:0050768), regulation of heart growth (GO:0060420), heart morphogenesis (GO:0003007), nervous system development (GO:0007399), epidermis development (GO:0008544), protein transport (GO:0015031), positive regulation of cardiac muscle tissue growth (GO:0055023), heterocycle biosynthetic process (GO:0018130), vasculogenesis (GO:0001570), central nervous system development (GO:0007417), negative regulation of glial cell proliferation (GO:0060253), inner ear receptor cell differentiation (GO:0060113), regulation of RNA metabolic process (GO:0051252), response to cytokine (GO:0034097), negative regulation of catalytic activity (GO:0043086), muscle tissue morphogenesis (GO:0060415), neural tube development (GO:0021915), positive regulation of programmed cell death (GO:0043068), positive regulation of epidermal cell differentiation (GO:0045606), regulation of nervous system development (GO:0051960), mesenchyme development (GO:0060485), negative regulation of neuron differentiation (GO:0045665), left/right axis specification (GO:0070986), digestive tract morphogenesis (GO:0048546), epithelial cell differentiation (GO:0030855), nucleobase-containing compound biosynthetic process (GO:0034654), regulation of biomineral tissue development (GO:0070167), determination of bilateral symmetry (GO:0009855), lung development (GO:0030324), stem cell differentiation (GO:0048863), mesenchyme morphogenesis (GO:0072132), myoblast differentiation (GO:0045445), blood vessel morphogenesis (GO:0048514), negative regulation of epithelial cell differentiation (GO:0030857), limb development (GO:0060173), regulation of secretion (GO:0051046), vesicle-mediated transport (GO:0016192), homeostasis of number of cells within a tissue (GO:0048873), negative regulation of RNA metabolic process (GO:0051253), kidney development (GO:0001822), anterior/posterior pattern specification (GO:0009952), regulation of apoptotic process (GO:0042981), negative regulation of gliogenesis (GO:0014014), striated muscle tissue development (GO:0014706), ear development (GO:0043583), cardiac left ventricle morphogenesis (GO:0003214), skeletal muscle tissue development (GO:0007519), ventricular trabecula myocardium morphogenesis (GO:0003222), regulation of oligodendrocyte differentiation (GO:0048713), liver development (GO:0001889), positive regulation of RNA biosynthetic process (GO:1902680), artery morphogenesis (GO:0048844), cardiac epithelial to mesenchymal transition (GO:0060317), nucleocytoplasmic transport (GO:0006913), regulation of astrocyte differentiation (GO:0048710), response to interleukin-17 (GO:0097396), positive regulation of BMP signaling pathway (GO:0030513), cardiac muscle tissue development (GO:0048738), photoreceptor cell differentiation (GO:0046530), kidney epithelium development (GO:0072073), endocardial cushion morphogenesis (GO:0003203), columnar/cuboidal epithelial cell differentiation (GO:0002065), gliogenesis (GO:0042063), neuron projection development (GO:0031175), endothelium development (GO:0003158), epidermal cell differentiation (GO:0009913), regulation of keratinocyte differentiation (GO:0045616), nucleic acid-templated transcription (GO:0097659), pericardium development (GO:0060039), mechanoreceptor differentiation (GO:0042490), determination of left/right symmetry (GO:0007368), pulmonary valve development (GO:0003177), eye morphogenesis (GO:0048592), hindlimb morphogenesis (GO:0035137), smooth muscle cell differentiation (GO:0051145), oligodendrocyte differentiation (GO:0048709), endocardial cushion development (GO:0003197), epidermis morphogenesis (GO:0048730), negative regulation of regulated secretory pathway (GO:1903306), regulation of neurogenesis (GO:0050767), negative regulation of canonical Wnt signaling pathway (GO:0090090), regulation of canonical Wnt signaling pathway (GO:0060828), inner ear auditory receptor cell differentiation (GO:0042491), cell morphogenesis involved in neuron differentiation (GO:0048667), skeletal muscle organ development (GO:0060538), regulation of striated muscle cell differentiation (GO:0051153), positive regulation of gliogenesis (GO:0014015), positive regulation of glial cell differentiation (GO:0045687)

Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), membrane (GO:0016020), membrane-enclosed lumen (GO:0031974), cytosol (GO:0005829), cell surface (GO:0009986), cell periphery (GO:0071944), cell junction (GO:0030054), organelle subcompartment (GO:0031984), apical part of cell (GO:0045177), cytoplasm (GO:0005737), endomembrane system (GO:0012505), nucleoplasm (GO:0005654), extracellular region (GO:0005576), organelle membrane (GO:0031090), cytoplasmic vesicle (GO:0031410), intracellular organelle (GO:0043229), apical plasma membrane (GO:0016324), endoplasmic reticulum subcompartment (GO:0098827), nuclear outer membrane-endoplasmic reticulum membrane network (GO:0042175), Golgi apparatus (GO:0005794), plasma membrane region (GO:0098590), organelle lumen (GO:0043233), endoplasmic reticulum (GO:0005783), anchoring junction (GO:0070161), membrane-bounded organelle (GO:0043227), plasma membrane (GO:0005886), intracellular membrane-bounded organelle (GO:0043231), bounding membrane of organelle (GO:0098588), endoplasmic reticulum membrane (GO:0005789), vesicle (GO:0031982), intracellular organelle lumen (GO:0070013), cell-cell junction (GO:0005911), Golgi membrane (GO:0000139), intracellular vesicle (GO:0097708), nucleus (GO:0005634), nuclear lumen (GO:0031981), adherens junction (GO:0005912)

Generated by BioReason

Deep Research Bioreason Rl

(Notch1-deep-research-bioreason-rl.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:24 AM

Organism: Mus musculus

Sequence:

MPRLLTPLLCLTLLPALAARGLRCSQPSGTCLNGGRCEVANGTEACVCSGAFVGQRCQDSNPCLSTPCKNAGTCHVVDHGGTVDYACSCPLGFSGPLCLTPLDNACLANPCRNGGTCDLLTLTEYKCRCPPGWSGKSCQQADPCASNPCANGGQCLPFESSYICRCPPGFHGPTCRQDVNECSQNPGLCRHGGTCHNEIGSYRCACRATHTGPHCELPYVPCSPSPCQNGGTCRPTGDTTHECACLPGFAGQNCEENVDDCPGNNCKNGGACVDGVNTYNCRCPPEWTGQYCTEDVDECQLMPNACQNGGTCHNTHGGYNCVCVNGWTGEDCSENIDDCASAACFQGATCHDRVASFYCECPHGRTGLLCHLNDACISNPCNEGSNCDTNPVNGKAICTCPSGYTGPACSQDVDECALGANPCEHAGKCLNTLGSFECQCLQGYTGPRCEIDVNECISNPCQNDATCLDQIGEFQCICMPGYEGVYCEINTDECASSPCLHNGHCMDKINEFQCQCPKGFNGHLCQYDVDECASTPCKNGAKCLDGPNTYTCVCTEGYTGTHCEVDIDECDPDPCHYGSCKDGVATFTCLCQPGYTGHHCETNINECHSQPCRHGGTCQDRDNSYLCLCLKGTTGPNCEINLDDCASNPCDSGTCLDKIDGYECACEPGYTGSMCNVNIDECAGSPCHNGGTCEDGIAGFTCRCPEGYHDPTCLSEVNECNSNPCIHGACRDGLNGYKCDCAPGWSGTNCDINNNECESNPCVNGGTCKDMTSGYVCTCREGFSGPNCQTNINECASNPCLNQGTCIDDVAGYKCNCPLPYTGATCEVVLAPCATSPCKNSGVCKESEDYESFSCVCPTGWQGQTCEVDINECVKSPCRHGASCQNTNGSYRCLCQAGYTGRNCESDIDDCRPNPCHNGGSCTDGINTAFCDCLPGFQGAFCEEDINECASNPCQNGANCTDCVDSYTCTCPVGFNGIHCENNTPDCTESSCFNGGTCVDGINSFTCLCPPGFTGSYCQYDVNECDSRPCLHGGTCQDSYGTYKCTCPQGYTGLNCQNLVRWCDSAPCKNGGRCWQTNTQYHCECRSGWTGVNCDVLSVSCEVAAQKRGIDVTLLCQHGGLCVDEGDKHYCHCQAGYTGSYCEDEVDECSPNPCQNGATCTDYLGGFSCKCVAGYHGSNCSEEINECLSQPCQNGGTCIDLTNSYKCSCPRGTQGVHCEINVDDCHPPLDPASRSPKCFNNGTCVDQVGGYTCTCPPGFVGERCEGDVNECLSNPCDPRGTQNCVQRVNDFHCECRAGHTGRRCESVINGCRGKPCKNGGVCAVASNTARGFICRCPAGFEGATCENDARTCGSLRCLNGGTCISGPRSPTCLCLGSFTGPECQFPASSPCVGSNPCYNQGTCEPTSENPFYRCLCPAKFNGLLCHILDYSFTGGAGRDIPPPQIEEACELPECQVDAGNKVCNLQCNNHACGWDGGDCSLNFNDPWKNCTQSLQCWKYFSDGHCDSQCNSAGCLFDGFDCQLTEGQCNPLYDQYCKDHFSDGHCDQGCNSAECEWDGLDCAEHVPERLAAGTLVLVVLLPPDQLRNNSFHFLRELSHVLHTNVVFKRDAQGQQMIFPYYGHEEELRKHPIKRSTVGWATSSLLPGTSGGRQRRELDPMDIRGSIVYLEIDNRQCVQSSSQCFQSATDVAAFLGALASLGSLNIPYKIEAVKSEPVEPPLPSQLHLMYVAAAAFVLLFFVGCGVLLSRKRRRQHGQLWFPEGFKVSEASKKKRREPLGEDSVGLKPLKNASDGALMDDNQNEWGDEDLETKKFRFEEPVVLPDLSDQTDHRQWTQQHLDAADLRMSAMAPTPPQGEVDADCMDVNVRGPDGFTPLMIASCSGGGLETGNSEEEEDAPAVISDFIYQGASLHNQTDRTGETALHLAARYSRSDAAKRLLEASADANIQDNMGRTPLHAAVSADAQGVFQILLRNRATDLDARMHDGTTPLILAARLAVEGM

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

Notch (IPR008297, family) — residues 5-2000
EGF-like domain (IPR000742, domain) — residues 20-1426
EGF-like calcium-binding domain (IPR001881, domain) — residues 59-1384
EGF-like calcium-binding, conserved site (IPR018097, conserved_site) — residues 178-1253
NOTCH1, EGF-like calcium-binding domain (IPR049883, domain) — residues 178-900
EGF-type aspartate/asparagine hydroxylation site (IPR000152, ptm) — residues 195-1255
Growth factor receptor cysteine-rich domain superfamily (IPR009030, homologous_superfamily) — residues 288-1311
EGF-like, conserved site (IPR013032, conserved_site) — residues 344-1374
Neurogenic locus notch homolog protein 1 (IPR022362, family) — residues 1426-1714
Notch domain (IPR000800, domain) — residues 1442-1571
Notch-like domain superfamily (IPR035993, homologous_superfamily) — residues 1448-1561
Notch, NOD domain (IPR010660, domain) — residues 1566-1622
Notch, NODP domain (IPR011656, domain) — residues 1660-1722
Ankyrin repeat-containing domain superfamily (IPR036770, homologous_superfamily) — residues 1858-2000
Ankyrin repeat (IPR002110, repeat) — residues 1870-1980

GO Terms

Generated by BioReason

Deep Research Falcon

(Notch1-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2026-05-03T14:31:33.192595'
end_time: '2026-05-03T14:48:07.898044'
duration_seconds: 994.71
template_file: templates/gene_research_go_focused.md
template_variables:
organism: mouse
gene_id: Notch1
gene_symbol: Notch1
uniprot_accession: Q01705
protein_description: 'RecName: Full=Neurogenic locus notch homolog protein 1; Short=Notch
1; AltName: Full=Motch A {ECO:0000303|PubMed:8440332}; AltName: Full=mT14; AltName:
Full=p300; Contains: RecName: Full=Notch 1 extracellular truncation {ECO:0000303|PubMed:10882062};
Short=NEXT {ECO:0000303|PubMed:10882062}; Contains: RecName: Full=Notch 1 intracellular
domain; Short=NICD; Flags: Precursor;'
gene_info: Name=Notch1; Synonyms=Motch {ECO:0000303|PubMed:8440332};
organism_full: Mus musculus (Mouse).
protein_family: Belongs to the NOTCH family. .
protein_domains: Ankyrin_rpt. (IPR002110); Ankyrin_rpt-contain_sf. (IPR036770);
EGF. (IPR000742); EGF-like_Ca-bd_dom. (IPR001881); EGF-like_CS. (IPR013032)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
temperature: 0.1
citation_count: 34

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q01705
Protein Description: RecName: Full=Neurogenic locus notch homolog protein 1; Short=Notch 1; AltName: Full=Motch A {ECO:0000303|PubMed:8440332}; AltName: Full=mT14; AltName: Full=p300; Contains: RecName: Full=Notch 1 extracellular truncation {ECO:0000303|PubMed:10882062}; Short=NEXT {ECO:0000303|PubMed:10882062}; Contains: RecName: Full=Notch 1 intracellular domain; Short=NICD; Flags: Precursor;
Gene Information: Name=Notch1; Synonyms=Motch {ECO:0000303|PubMed:8440332};
Organism (full): Mus musculus (Mouse).
Protein Family: Belongs to the NOTCH family. .
Key Domains: Ankyrin_rpt. (IPR002110); Ankyrin_rpt-contain_sf. (IPR036770); EGF. (IPR000742); EGF-like_Ca-bd_dom. (IPR001881); EGF-like_CS. (IPR013032)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "Notch1" matches the protein description above
Verify the organism is correct: Mus musculus (Mouse).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'Notch1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene Notch1 (gene ID: Notch1, UniProt: Q01705) in mouse.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q01705
Protein Description: RecName: Full=Neurogenic locus notch homolog protein 1; Short=Notch 1; AltName: Full=Motch A {ECO:0000303|PubMed:8440332}; AltName: Full=mT14; AltName: Full=p300; Contains: RecName: Full=Notch 1 extracellular truncation {ECO:0000303|PubMed:10882062}; Short=NEXT {ECO:0000303|PubMed:10882062}; Contains: RecName: Full=Notch 1 intracellular domain; Short=NICD; Flags: Precursor;
Gene Information: Name=Notch1; Synonyms=Motch {ECO:0000303|PubMed:8440332};
Organism (full): Mus musculus (Mouse).
Protein Family: Belongs to the NOTCH family. .
Key Domains: Ankyrin_rpt. (IPR002110); Ankyrin_rpt-contain_sf. (IPR036770); EGF. (IPR000742); EGF-like_Ca-bd_dom. (IPR001881); EGF-like_CS. (IPR013032)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "Notch1" matches the protein description above
Verify the organism is correct: Mus musculus (Mouse).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene Notch1 (gene ID: Notch1, UniProt: Q01705) in mouse.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research Report: Functional Annotation of Mouse Notch1 (UniProt Q01705)

0) Target verification (mandatory)

The target is Notch1 from Mus musculus (mouse), UniProt accession Q01705, described as Neurogenic locus notch homolog protein 1 (Notch 1), a canonical NOTCH-family single-pass transmembrane receptor with a large EGF-repeat extracellular domain and an intracellular ankyrin-repeat signaling domain. The domain architecture and activation mechanism described in recent authoritative sources (EGF repeats; NRR with LNR+HD; intracellular RAM/ANK/TAD/PEST; cleavage to NEXT/NICD) match the NOTCH-family/domain expectations given in the user-provided UniProt context, supporting correct gene/protein identification. (sanlidag2025molecularandtissuelevel pages 19-22, bray2025modesofnotch pages 27-33, czerwonka2023modulationofnotch pages 1-3)

1) Key concepts and definitions (current understanding)

1.1 Notch signaling is juxtacrine and force dependent

Notch signaling is a cell–cell contact (juxtacrine) pathway in which a membrane-tethered ligand (DLL/Delta-like or Jagged) on a “sending” cell binds Notch receptors on an adjacent “receiving” cell; ligand endocytosis generates a pulling force that opens the receptor’s negative regulatory region (NRR) and enables proteolytic activation. (lv2024evolutionandfunction pages 2-4, bray2025modesofnotch pages 27-33, bray2025modesofnotch media f72360ab)

1.2 Protein architecture (functional modules)

Mouse Notch1 is a type I transmembrane receptor whose extracellular domain contains multiple EGF-like repeats involved in ligand binding and specificity. A membrane-proximal NRR (negative regulatory region) composed of three LNR repeats plus a heterodimerization (HD) domain protects the receptor from ligand-independent cleavage by masking the S2 site. The intracellular domain (NICD) contains a RAM region (high-affinity CSL/RBPJ binding), seven ankyrin repeats (ANK), a transactivation domain (TAD), and a C-terminal PEST motif that promotes turnover. (sanlidag2025molecularandtissuelevel pages 19-22, czerwonka2023modulationofnotch pages 1-3, sen2023theintricatenotch pages 1-2, bray2025modesofnotch media 3ef0fbcb)

1.3 Canonical activation mechanism and key cleavage steps (S1/S2/S3)

Notch1 activation is mediated by sequential proteolysis:
- S1 cleavage by a furin-like convertase in the Golgi yields a mature heterodimeric receptor that localizes at the plasma membrane. (sanlidag2025molecularandtissuelevel pages 19-22, lv2024evolutionandfunction pages 2-4, wang2024mechanismofnotch pages 3-5)
- S2 cleavage is performed by ADAM metalloproteases (ADAM10/ADAM17) after ligand-dependent opening of the NRR; this produces the membrane-tethered intermediate called NEXT (Notch extracellular truncation). (sanlidag2025molecularandtissuelevel pages 19-22, lv2024evolutionandfunction pages 2-4, wang2024mechanismofnotch pages 3-5, bray2025modesofnotch media f72360ab)
- S3 cleavage by γ-secretase releases the NICD. In mouse Notch1, a key S3-adjacent residue highlighted in recent literature is V1744 (mouse numbering). (sanlidag2025molecularandtissuelevel pages 19-22, medina2023newtricksfor pages 2-4)

After S3 cleavage, NICD translocates to the nucleus, switching Notch from a membrane receptor to a transcriptional effector. (sanlidag2025molecularandtissuelevel pages 19-22, lv2024evolutionandfunction pages 2-4, wang2024mechanismofnotch pages 3-5, bray2025modesofnotch media f72360ab)

1.4 Nuclear transcriptional complex and canonical targets

In the nucleus, NICD binds the DNA-binding transcription factor CSL/RBPJ and recruits MAML (Mastermind-like) to form an activating complex that drives transcription of canonical Notch targets. Canonical target gene families include Hes and Hey (e.g., Hes1, Hes5, Hey1). (sanlidag2025molecularandtissuelevel pages 19-22, lv2024evolutionandfunction pages 2-4, wang2024mechanismofnotch pages 3-5, bray2025modesofnotch pages 27-33)

1.5 Subcellular localization summary

Notch1 is synthesized in the ER, processed in the Golgi (including S1 cleavage), then functions at the plasma membrane as a heterodimeric receptor. Upon activation, the NICD relocates to the nucleus; in some contexts, S3 cleavage and signaling can involve endocytic compartments. (sanlidag2025molecularandtissuelevel pages 19-22, lv2024evolutionandfunction pages 2-4, wang2024mechanismofnotch pages 3-5, feng2024thestructuraland pages 21-25)

2) Recent developments and latest research (prioritizing 2023–2024)

2.1 Vascular homeostasis: Dll4 loss does not phenocopy Notch1/Rbpj loss (adult endothelium)

A 2023 Nature Cardiovascular Research study systematically compared genetic perturbations across Notch pathway members in adult mouse endothelium and reported that Dll4 loss triggers a strong Myc-driven transcriptional switch toward proliferation and endothelial “tip-cell” programs, whereas Notch1 or Rbpj loss yields a distinct vascular cell state characterized by MAPK activation (p-ERK), p21 upregulation, enlarged nuclei, binucleation, and signatures consistent with replicative stress/senescence. Importantly, EC-specific expression of Notch1 intracellular domain (N1ICD) could rescue Dll4-loss vascular pathology, and Myc deletion largely suppressed the Dll4-driven proliferative/tip-cell transcriptional program but did not fully prevent abnormal dilated vessels and pathology, indicating a separation between transcriptional state and tissue-level phenotype. (Apr 2023; https://doi.org/10.1038/s44161-023-00272-4) (fernandezchacon2023incongruencebetweentranscriptional pages 5-6, fernandezchacon2023incongruencebetweentranscriptional pages 7-8, fernandezchacon2023incongruencebetweentranscriptional pages 4-5)

2.2 Brain endothelium/BBB integrity: DLL4–NOTCH1–CLDN5 axis and hyperoxia vulnerability

Ke et al. (Apr 2024) dissected a DLL4–NOTCH–CLDN5 pathway in developing mouse brain endothelium. They provided mechanistic evidence that NOTCH1 binds the CLDN5 promoter at an RBPJ site (ChIP; P=0.014) and that NICD increases CLDN5 promoter activity (luciferase; P≈0.0058–0.0059). Pharmacologic γ-secretase inhibition (DAPT/DBZ) reduced CLDN5 mRNA by ~40–45% and reduced the Notch target HEY1 by ~70–75% (P<0.0001), supporting CLDN5 as a Notch-dependent barrier gene in brain endothelium. In vivo neonatal hyperoxia (85% FiO2, P1–P14) reduced vascular CD31 density in multiple brain regions and decreased Dll4 expression (sex-stratified p-values reported), linking oxygen stress to suppressed DLL4/Notch signaling and impaired vascular development. (Apr 2024; https://doi.org/10.1113/jp285716) (ke2024deltalike4 pages 14-15, ke2024deltalike4 pages 15-15, ke2024deltalike4 pages 11-12)

2.3 CNS neuroinflammation: astrocytic DLL4–NOTCH1 drives IL-6/STAT3 reactivity and BBB dysfunction

Mora et al. (Oct 2024) report that in neuroinflammatory contexts, astrocytic DLL4 is upregulated and signals through NOTCH1 on neighboring astrocytes, driving IL-6 expression and STAT3 phosphorylation (pSTAT3), increasing astrocyte reactivity markers and secretion of pro-permeability factors, thereby destabilizing the BBB and promoting inflammatory infiltration. In mouse EAE and an acute IL-1β lesion model, astrocyte-specific Dll4 inactivation reduced IL-6/pSTAT3 and was associated with reduced BBB disruption and inflammatory infiltration; antibody-mediated DLL4 blockade improved EAE symptoms, highlighting a potentially actionable DLL4–NOTCH1 axis in CNS inflammation. (Oct 2024; https://doi.org/10.1186/s12974-024-03246-w) (mora2024astrocyticdll4notch1signaling pages 9-12, mora2024astrocyticdll4notch1signaling pages 1-2)

2.4 Metabolism/cancer cachexia: endothelial Notch1 in adipose tissue as a long-range wasting driver

Taylor et al. (Nature Cancer, Sep 2023) established that tumors can remotely overactivate Notch1 signaling in distant WAT endothelium during precachexia; sustained endothelial Notch1 activation was sufficient to induce a WAT-wasting phenotype mediated by increased retinoic acid (RA) production. In vivo, endothelial Notch activation was linked to elevated IL-33, increased ALDH activity in WAT myeloid populations, and transcriptional induction of RA targets (including Igfbp3). A key translational finding was that downstream targeting of RA signaling with the pan-RAR antagonist BMS493 (oral; 5 mg/kg every other day) in a KPC tumor-bearing cachexia model prevented WAT loss and adipocyte size changes without reducing tumor mass (reported n=5–6 per group). (Sep 2023; https://doi.org/10.1038/s43018-023-00622-y) (taylor2023endothelialnotch1signaling pages 10-11, taylor2023endothelialnotch1signaling pages 1-2, taylor2023endothelialnotch1signaling pages 11-12, taylor2023endothelialnotch1signaling pages 5-6)

2.5 Immune function in vivo: Notch receptor signaling in CD4+ T cells during tissue repair

Melvin et al. (Aug 2024, JCI Insight) linked Notch receptor signaling to CD4+ T cell differentiation during wound repair in mouse models, with epigenetic regulation by MLL1 increasing Notch receptor expression and Notch signaling. They reported that loss of upstream Notch pathway mediators or receptors in CD4+ T cells resulted in loss of Th differentiation in wounds, and that in diabetes, Notch signaling is upregulated in wound CD4+ T cells promoting Th17 skewing; MLL1 inhibition reduced Th17 cells and IL-17A. (Aug 2024; https://doi.org/10.1172/jci.insight.179012) (melvin2024thehistonemethyltransferase pages 1-2)

3) Functional annotation: primary molecular function, pathways, localization

3.1 Primary molecular function (signaling role)

Notch1 is not an enzyme or transporter; its primary function is as a mechanosensitive receptor that converts extracellular ligand binding into nuclear transcriptional regulation by releasing NICD, which then reprograms gene expression via CSL/RBPJ and MAML. (lv2024evolutionandfunction pages 2-4, wang2024mechanismofnotch pages 3-5, bray2025modesofnotch pages 27-33)

3.2 Pathway placement and core steps (mouse Notch1)

A concise pathway view:
1) Membrane Notch1 binds a neighboring ligand (DLL4/Jagged). (bray2025modesofnotch pages 27-33, bray2025modesofnotch media f72360ab)
2) Mechanical activation opens NRR → ADAM10/17 S2 cleavage → NEXT. (sanlidag2025molecularandtissuelevel pages 19-22, lv2024evolutionandfunction pages 2-4, bray2025modesofnotch media f72360ab)
3) γ-secretase S3 cleavage (mouse residue context includes V1744) → NICD release. (sanlidag2025molecularandtissuelevel pages 19-22, medina2023newtricksfor pages 2-4)
4) NICD nuclear entry and assembly with CSL/RBPJ + MAML → transcription of targets such as Hes/Hey. (sanlidag2025molecularandtissuelevel pages 19-22, lv2024evolutionandfunction pages 2-4, wang2024mechanismofnotch pages 3-5)

A visual schematic of these steps and the domain architecture is available in the retrieved figure crops. (bray2025modesofnotch media f72360ab, bray2025modesofnotch media 3ef0fbcb)

3.3 Protein turnover and signal termination

The PEST domain promotes NICD degradation (e.g., phosphorylation/ubiquitylation pathways including FBXW7-mediated turnover), providing temporal control of Notch1 signaling. (sanlidag2025molecularandtissuelevel pages 19-22, lv2024evolutionandfunction pages 2-4, wang2024mechanismofnotch pages 3-5)

4) Current applications and real-world implementations

4.1 Therapeutic modulation strategies (expert review synthesis)

Recent reviews emphasize that Notch can be modulated at multiple points: receptor/ligand interactions, ADAM cleavage, γ-secretase cleavage, receptor trafficking/glycosylation, and nuclear transcription complex formation. (Sep 2023; https://doi.org/10.3390/cancers15184563) (czerwonka2023modulationofnotch pages 1-3)
A 2023 Trends in Pharmacological Sciences review highlights emerging Notch-based biotechnologies and therapeutics, including structural insights into proteolysis and strategies to target the NICD–CSL–MAML complex with inhibitory compounds (e.g., CB-103 and others mentioned), illustrating the push toward more selective pathway control beyond pan–γ-secretase blockade. (Dec 2023; https://doi.org/10.1016/j.tips.2023.09.011) (medina2023newtricksfor pages 2-4)

4.2 Receptor-selective targeting: anti-Notch1 antibody in melanoma models (2024)

De Freitas et al. (Nov 2024) developed a selective anti-Notch1 neutralizing antibody that reduced cleaved Notch1 (NICD) in a dose-dependent manner and showed strong direct anti-melanoma effects.
- In vitro, 72 h treatment caused ~75% (K457), ~80% (YUMM1.7), and ~55% (YUMM2.1) melanoma cell death at 25 μg/ml; multiple other human lines showed substantial killing, and 3D spheroids showed ~4-fold shifts toward cell death. (freitas2024notch1blockadeby pages 7-10, freitas2024notch1blockadeby pages 5-7)
- In vivo (syngeneic YUMM2.1), dosing was 10 mg/kg i.p. every other day; anti-Notch1 delayed tumor growth and reshaped the tumor immune microenvironment (reduced MDSCs and Tregs; increased CD8+ T cells). Combination therapy with anti-PD-1 produced sustained separation in tumor growth by day 22. (Nov 2024; https://doi.org/10.1186/s13046-024-03214-5) (freitas2024notch1blockadeby pages 7-10, freitas2024notch1blockadeby pages 10-12)
This study provides a concrete example of receptor-specific pathway targeting intended to mitigate the toxicity of broader Notch inhibition while maintaining anti-tumor activity. (freitas2024notch1blockadeby pages 7-10, freitas2024notch1blockadeby pages 5-7)

4.3 Targeting downstream effector pathways: RA blockade in cachexia (2023)

Taylor et al. show a “downstream” approach: pharmacologic blockade of RA signaling (BMS493) prevented WAT loss in tumor-bearing mice without affecting tumor mass, demonstrating how mechanistic functional annotation can guide selection of intervention points with potentially improved tolerability. (Sep 2023; https://doi.org/10.1038/s43018-023-00622-y) (taylor2023endothelialnotch1signaling pages 10-11)

5) Relevant statistics and quantitative data (from recent studies)

Brain endothelium: γ-secretase inhibition decreased CLDN5 mRNA by ~40–45% and reduced HEY1 by ~70–75% (P<0.0001; three experiments). (Ke et al., Apr 2024; https://doi.org/10.1113/jp285716) (ke2024deltalike4 pages 15-15)
BBB leak with DLL4 insufficiency: Dll4 haploinsufficiency increased brain albumin at P21 (sex-specific p-values reported) and increased permeability readouts in vitro (TEER decreased; FITC-dextran permeability increased). (Ke et al., Apr 2024; https://doi.org/10.1113/jp285716) (ke2024deltalike4 pages 11-12, ke2024deltalike4 pages 11-11)
Melanoma cytotoxicity (anti-Notch1): ~55–80% cell death across multiple melanoma lines after 72 h at 25 μg/ml; ~80% reduction in clonogenic growth; ~4-fold increase in dead cells in spheroids. (de Freitas et al., Nov 2024; https://doi.org/10.1186/s13046-024-03214-5) (freitas2024notch1blockadeby pages 7-10, freitas2024notch1blockadeby pages 5-7)
Cachexia intervention: pan-RAR antagonist BMS493 prevented WAT loss/adipocyte shrinkage in KPC-bearing mice with n=5–6 per group for key readouts and no tumor mass difference reported. (Taylor et al., Sep 2023; https://doi.org/10.1038/s43018-023-00622-y) (taylor2023endothelialnotch1signaling pages 10-11)

6) Expert interpretation and synthesis (authoritative perspective)

6.1 Why Notch1 is “context-dependent” yet mechanistically precise

A recurring expert conclusion is that the core Notch mechanism (force-dependent proteolysis → NICD → CSL/MAML transcription) is highly conserved and molecularly well-defined, but biological outcomes depend on (i) which ligand is presented (DLL vs Jagged), (ii) receptor post-translational processing/trafficking and NRR conformational control, and (iii) the chromatin/transcriptional environment of a given cell type. (lv2024evolutionandfunction pages 2-4, wang2024mechanismofnotch pages 3-5, bray2025modesofnotch pages 27-33)

The 2023 adult vascular genetics study highlights that inhibiting a ligand (Dll4) can push endothelium into a Myc-driven proliferative program, whereas Notch1/Rbpj loss can yield a MAPK/p21/senescence-like phenotype. This strengthens the interpretation that in vivo Notch pathway “nodes” are not equivalent intervention points; receptor- vs ligand- vs downstream targeting can yield meaningfully different outcomes. (fernandezchacon2023incongruencebetweentranscriptional pages 5-6, fernandezchacon2023incongruencebetweentranscriptional pages 7-8)

7) Summary evidence map (for functional annotation)

Category	Key points	Key sources (citation IDs)
Identity	Mouse Notch1 / UniProt Q01705 is the NOTCH-family type I single-pass transmembrane receptor. Domain architecture includes a large extracellular region with multiple EGF repeats, a negative regulatory region (NRR) composed of LNR + heterodimerization (HD) modules, a transmembrane segment, and an intracellular region containing RAM, ankyrin repeats (ANK), TAD, and PEST motifs.	(sanlidag2025molecularandtissuelevel pages 19-22, bray2025modesofnotch pages 27-33, czerwonka2023modulationofnotch pages 1-3, sen2023theintricatenotch pages 1-2)
Localization	Newly synthesized receptor traffics through ER/Golgi, undergoes maturation, and localizes as a heterodimer at the plasma membrane. After activation, the cleaved intracellular fragment (NICD) relocalizes to the nucleus; signaling can also involve endocytic compartments.	(sanlidag2025molecularandtissuelevel pages 19-22, lv2024evolutionandfunction pages 2-4, wang2024mechanismofnotch pages 3-5, feng2024thestructuraland pages 21-25)
Activation	Canonical activation is juxtacrine: ligand binding plus mechanical pulling exposes the NRR for proteolysis. S1 cleavage occurs in the Golgi by a furin-like convertase; S2 cleavage is mediated mainly by ADAM10/ADAM17; S3 cleavage is mediated by γ-secretase, releasing NICD. For mouse Notch1, the S3-adjacent cleavage residue highlighted in the literature is V1744.	(sanlidag2025molecularandtissuelevel pages 19-22, lv2024evolutionandfunction pages 2-4, wang2024mechanismofnotch pages 3-5, medina2023newtricksfor pages 2-4, bray2025modesofnotch media f72360ab)
Partners	Canonical nuclear signaling uses RBPJ/CSL DNA-binding factor plus MAML co-activator; RAM and ANK mediate key interactions, and additional co-activators such as CBP/p300, PCAF/GCN5, SKIP, mediator/NACK can contribute in context.	(sanlidag2025molecularandtissuelevel pages 19-22, wang2024mechanismofnotch pages 3-5, medina2023newtricksfor pages 2-4, sen2023theintricatenotch pages 1-2)
Canonical targets	Best-established direct/near-direct transcriptional outputs include Hes and Hey family genes (especially Hes1, Hes5, Hey1), consistent with Notch1 function in fate maintenance and suppression of alternative differentiation programs.	(sanlidag2025molecularandtissuelevel pages 19-22, lv2024evolutionandfunction pages 2-4, wang2024mechanismofnotch pages 3-5, bray2025modesofnotch pages 27-33)
Selected 2023-2024 in vivo functions	Vasculature: adult endothelial Dll4 loss triggers a strong Myc-driven tip-cell/proliferative program, whereas Notch1/Rbpj loss yields a distinct MAPK/p21/senescence-like state; Notch1 activity is therefore central to endothelial homeostasis but not identical to Dll4 loss phenotypes. Brain endothelium/CNS: DLL4-NOTCH1-CLDN5 signaling supports cerebrovascular integrity; Dll4 insufficiency increases BBB leak and reduces CLDN5/HEY1 outputs, while astrocytic DLL4-NOTCH1 promotes IL-6/STAT3-dependent neuroinflammation and BBB destabilization in EAE. Immune/wound repair: Notch receptor signaling is required for CD4+ T-cell differentiation in wounds and is upregulated in diabetic wound inflammation. Metabolism/cachexia: sustained endothelial Notch1 activation in WAT drives adipose wasting, inflammation/beiging/fibrosis programs, and retinoic-acid-linked remodeling; downstream RAR antagonism can prevent WAT loss in mouse cachexia models.	(fernandezchacon2023incongruencebetweentranscriptional pages 5-6, fernandezchacon2023incongruencebetweentranscriptional pages 7-8, ke2024deltalike4 pages 15-15, ke2024deltalike4 pages 11-12, ke2024deltalike4 pages 11-11, mora2024astrocyticdll4notch1signaling pages 9-12, melvin2024thehistonemethyltransferase pages 1-2, taylor2023endothelialnotch1signaling pages 10-11, taylor2023endothelialnotch1signaling pages 5-6)
Applications	Research models: inducible endothelial, astrocytic, and immune-cell mouse models are widely used to dissect cell-type-specific Notch1 biology. Therapeutic targeting: receptor-proximal blockade (anti-NOTCH1 antibodies), ligand blockade, γ-secretase inhibition, and downstream pathway targeting are active strategies. A 2024 selective anti-Notch1 antibody reduced melanoma cell death-resistant signaling, delayed tumor growth, increased CD8+ infiltration, and improved anti-PD-1 responses in mouse models, illustrating receptor-specific translational potential.	(medina2023newtricksfor pages 2-4, peng2023roleofthe pages 1-2, freitas2024notch1blockadeby pages 7-10, freitas2024notch1blockadeby pages 10-12, freitas2024notch1blockadeby pages 5-7)

Table: This table summarizes core functional annotation points for mouse Notch1 (UniProt Q01705), including structure, localization, activation mechanism, transcriptional partners, canonical targets, recent in vivo functions, and translational applications. It is designed as a compact evidence map for report writing and citation tracing.

8) Retrieved visual evidence (schematic)

A schematic overview of receptor domains and activation steps (ligand binding, ADAM10 S2 cleavage, γ-secretase S3 cleavage, NICD nuclear entry and CSL/MAML transcriptional complex) is shown in the retrieved figure crops. (bray2025modesofnotch media f72360ab, bray2025modesofnotch media 3ef0fbcb)

References (URLs and publication dates)

The following are the key 2023–2024 sources used (all cited in-text above):
- Fernández-Chacón M. et al. Nature Cardiovascular Research (Apr 2023). https://doi.org/10.1038/s44161-023-00272-4 (fernandezchacon2023incongruencebetweentranscriptional pages 5-6, fernandezchacon2023incongruencebetweentranscriptional pages 7-8)
- Taylor J. et al. Nature Cancer (Sep 2023). https://doi.org/10.1038/s43018-023-00622-y (taylor2023endothelialnotch1signaling pages 10-11, taylor2023endothelialnotch1signaling pages 5-6)
- Czerwonka A. et al. Cancers (Sep 2023). https://doi.org/10.3390/cancers15184563 (czerwonka2023modulationofnotch pages 1-3)
- Medina E. et al. Trends in Pharmacological Sciences (Dec 2023). https://doi.org/10.1016/j.tips.2023.09.011 (medina2023newtricksfor pages 2-4)
- Ke X. et al. The Journal of Physiology (Apr 2024). https://doi.org/10.1113/jp285716 (ke2024deltalike4 pages 15-15, ke2024deltalike4 pages 11-12)
- Melvin WJ. et al. JCI Insight (Aug 2024). https://doi.org/10.1172/jci.insight.179012 (melvin2024thehistonemethyltransferase pages 1-2)
- Mora P. et al. Journal of Neuroinflammation (Oct 2024). https://doi.org/10.1186/s12974-024-03246-w (mora2024astrocyticdll4notch1signaling pages 9-12)
- de Freitas JT. et al. Journal of Experimental & Clinical Cancer Research (Nov 2024). https://doi.org/10.1186/s13046-024-03214-5 (freitas2024notch1blockadeby pages 7-10, freitas2024notch1blockadeby pages 10-12)

(Additional mechanistic reviews used to support definitions and molecular details: Lv 2024 IJMS; Wang 2024 Biomolecules; Sen 2023 ACS PTS; Bray & Bigas 2025 Nat Rev Mol Cell Biol figure.) (lv2024evolutionandfunction pages 2-4, wang2024mechanismofnotch pages 3-5, sen2023theintricatenotch pages 1-2, bray2025modesofnotch media f72360ab)

References

(sanlidag2025molecularandtissuelevel pages 19-22): S Sanlidag. Molecular and tissue-level insights into jagged1-notch signaling. Unknown journal, 2025.
(bray2025modesofnotch pages 27-33): Sarah J. Bray and Anna Bigas. Modes of notch signalling in development and disease. Nature reviews. Molecular cell biology, 26:522-537, Mar 2025. URL: https://doi.org/10.1038/s41580-025-00835-2, doi:10.1038/s41580-025-00835-2. This article has 38 citations.
(czerwonka2023modulationofnotch pages 1-3): Arkadiusz Czerwonka, Joanna Kałafut, and Matthias Nees. Modulation of notch signaling by small-molecular compounds and its potential in anticancer studies. Cancers, 15:4563, Sep 2023. URL: https://doi.org/10.3390/cancers15184563, doi:10.3390/cancers15184563. This article has 15 citations.
(lv2024evolutionandfunction pages 2-4): Yan Lv, Xuan Pang, Zhonghong Cao, Changping Song, Baohua Liu, Weiwei Wu, and Qiuxiang Pang. Evolution and function of the notch signaling pathway: an invertebrate perspective. International Journal of Molecular Sciences, 25:3322, Mar 2024. URL: https://doi.org/10.3390/ijms25063322, doi:10.3390/ijms25063322. This article has 24 citations.
(bray2025modesofnotch media f72360ab): Sarah J. Bray and Anna Bigas. Modes of notch signalling in development and disease. Nature reviews. Molecular cell biology, 26:522-537, Mar 2025. URL: https://doi.org/10.1038/s41580-025-00835-2, doi:10.1038/s41580-025-00835-2. This article has 38 citations.
(sen2023theintricatenotch pages 1-2): Plaboni Sen and Siddhartha Sankar Ghosh. The intricate notch signaling dynamics in therapeutic realms of cancer. ACS pharmacology & translational science, 6 5:651-670, May 2023. URL: https://doi.org/10.1021/acsptsci.2c00239, doi:10.1021/acsptsci.2c00239. This article has 21 citations and is from a peer-reviewed journal.
(bray2025modesofnotch media 3ef0fbcb): Sarah J. Bray and Anna Bigas. Modes of notch signalling in development and disease. Nature reviews. Molecular cell biology, 26:522-537, Mar 2025. URL: https://doi.org/10.1038/s41580-025-00835-2, doi:10.1038/s41580-025-00835-2. This article has 38 citations.
(wang2024mechanismofnotch pages 3-5): Shenghao Wang, Sikuan Gu, Junfan Chen, Zhiqiang Yuan, Ping Liang, and Hongjuan Cui. Mechanism of notch signaling pathway in malignant progression of glioblastoma and targeted therapy. Biomolecules, 14:480, Apr 2024. URL: https://doi.org/10.3390/biom14040480, doi:10.3390/biom14040480. This article has 21 citations.
(medina2023newtricksfor pages 2-4): Elliot Medina, David H. Perez, Daniel Antfolk, and Vincent C. Luca. New tricks for an old pathway: emerging notch-based biotechnologies and therapeutics. Trends in Pharmacological Sciences, 44:934-948, Dec 2023. URL: https://doi.org/10.1016/j.tips.2023.09.011, doi:10.1016/j.tips.2023.09.011. This article has 14 citations and is from a highest quality peer-reviewed journal.
(feng2024thestructuraland pages 21-25): X Feng. The structural and functional significance of lipid-binding properties of human notch ligands. Unknown journal, 2024.
(fernandezchacon2023incongruencebetweentranscriptional pages 5-6): Macarena Fernández-Chacón, Severin Mühleder, Álvaro Regano, Lourdes Garcia-Ortega, Carlos Torroja, Mariya Lytvyn, Maria S Sanchez-Muñoz, Verónica Casquero-Garcia, Emilio Camafeita, Jesus Vazquez, Alberto Benguría, Ana Dopazo, Fátima Sánchez-Cabo, Hannah Carter, and Rui Benedito. Incongruence between transcriptional and vascular pathophysiological cell states. Nature cardiovascular research, 2:2023530-549, Apr 2023. URL: https://doi.org/10.1038/s44161-023-00272-4, doi:10.1038/s44161-023-00272-4. This article has 12 citations and is from a peer-reviewed journal.
(fernandezchacon2023incongruencebetweentranscriptional pages 7-8): Macarena Fernández-Chacón, Severin Mühleder, Álvaro Regano, Lourdes Garcia-Ortega, Carlos Torroja, Mariya Lytvyn, Maria S Sanchez-Muñoz, Verónica Casquero-Garcia, Emilio Camafeita, Jesus Vazquez, Alberto Benguría, Ana Dopazo, Fátima Sánchez-Cabo, Hannah Carter, and Rui Benedito. Incongruence between transcriptional and vascular pathophysiological cell states. Nature cardiovascular research, 2:2023530-549, Apr 2023. URL: https://doi.org/10.1038/s44161-023-00272-4, doi:10.1038/s44161-023-00272-4. This article has 12 citations and is from a peer-reviewed journal.
(fernandezchacon2023incongruencebetweentranscriptional pages 4-5): Macarena Fernández-Chacón, Severin Mühleder, Álvaro Regano, Lourdes Garcia-Ortega, Carlos Torroja, Mariya Lytvyn, Maria S Sanchez-Muñoz, Verónica Casquero-Garcia, Emilio Camafeita, Jesus Vazquez, Alberto Benguría, Ana Dopazo, Fátima Sánchez-Cabo, Hannah Carter, and Rui Benedito. Incongruence between transcriptional and vascular pathophysiological cell states. Nature cardiovascular research, 2:2023530-549, Apr 2023. URL: https://doi.org/10.1038/s44161-023-00272-4, doi:10.1038/s44161-023-00272-4. This article has 12 citations and is from a peer-reviewed journal.
(ke2024deltalike4 pages 14-15): Xingrao Ke, Sheng Xia, Wei Yu, Sherry Mabry, Qi Fu, Heather L. Menden, Venkatesh Sampath, and Robert H. Lane. Delta like 4 regulates cerebrovascular development and endothelial integrity via dll4‐notch‐cldn5 pathway and is vulnerable to neonatal hyperoxia. The Journal of Physiology, 602:2265-2285, Apr 2024. URL: https://doi.org/10.1113/jp285716, doi:10.1113/jp285716. This article has 8 citations.
(ke2024deltalike4 pages 15-15): Xingrao Ke, Sheng Xia, Wei Yu, Sherry Mabry, Qi Fu, Heather L. Menden, Venkatesh Sampath, and Robert H. Lane. Delta like 4 regulates cerebrovascular development and endothelial integrity via dll4‐notch‐cldn5 pathway and is vulnerable to neonatal hyperoxia. The Journal of Physiology, 602:2265-2285, Apr 2024. URL: https://doi.org/10.1113/jp285716, doi:10.1113/jp285716. This article has 8 citations.
(ke2024deltalike4 pages 11-12): Xingrao Ke, Sheng Xia, Wei Yu, Sherry Mabry, Qi Fu, Heather L. Menden, Venkatesh Sampath, and Robert H. Lane. Delta like 4 regulates cerebrovascular development and endothelial integrity via dll4‐notch‐cldn5 pathway and is vulnerable to neonatal hyperoxia. The Journal of Physiology, 602:2265-2285, Apr 2024. URL: https://doi.org/10.1113/jp285716, doi:10.1113/jp285716. This article has 8 citations.
(mora2024astrocyticdll4notch1signaling pages 9-12): Pierre Mora, Margaux Laisné, Célia Bourguignon, Paul Rouault, Béatrice Jaspard-Vinassa, Marlène Maître, Alain-Pierre Gadeau, Marie-Ange Renault, Sam Horng, Thierry Couffinhal, and Candice Chapouly. Astrocytic dll4-notch1 signaling pathway promotes neuroinflammation via the il-6-stat3 axis. Journal of Neuroinflammation, Oct 2024. URL: https://doi.org/10.1186/s12974-024-03246-w, doi:10.1186/s12974-024-03246-w. This article has 14 citations and is from a peer-reviewed journal.
(mora2024astrocyticdll4notch1signaling pages 1-2): Pierre Mora, Margaux Laisné, Célia Bourguignon, Paul Rouault, Béatrice Jaspard-Vinassa, Marlène Maître, Alain-Pierre Gadeau, Marie-Ange Renault, Sam Horng, Thierry Couffinhal, and Candice Chapouly. Astrocytic dll4-notch1 signaling pathway promotes neuroinflammation via the il-6-stat3 axis. Journal of Neuroinflammation, Oct 2024. URL: https://doi.org/10.1186/s12974-024-03246-w, doi:10.1186/s12974-024-03246-w. This article has 14 citations and is from a peer-reviewed journal.
(taylor2023endothelialnotch1signaling pages 10-11): Jacqueline Taylor, Leonie Uhl, Iris Moll, Sana Safatul Hasan, Lena Wiedmann, Jakob Morgenstern, Benedetto Daniele Giaimo, Tobias Friedrich, Elisenda Alsina-Sanchis, Francesca De Angelis Rigotti, Ronja Mülfarth, Sarah Kaltenbach, Darius Schenk, Felix Nickel, Thomas Fleming, David Sprinzak, Carolin Mogler, Thomas Korff, Adrian T. Billeter, Beat P. Müller-Stich, Mauricio Berriel Diaz, Tilman Borggrefe, Stephan Herzig, Maria Rohm, Juan Rodriguez-Vita, and Andreas Fischer. Endothelial notch1 signaling in white adipose tissue promotes cancer cachexia. Nature Cancer, 4:1544-1560, Sep 2023. URL: https://doi.org/10.1038/s43018-023-00622-y, doi:10.1038/s43018-023-00622-y. This article has 26 citations and is from a highest quality peer-reviewed journal.
(taylor2023endothelialnotch1signaling pages 1-2): Jacqueline Taylor, Leonie Uhl, Iris Moll, Sana Safatul Hasan, Lena Wiedmann, Jakob Morgenstern, Benedetto Daniele Giaimo, Tobias Friedrich, Elisenda Alsina-Sanchis, Francesca De Angelis Rigotti, Ronja Mülfarth, Sarah Kaltenbach, Darius Schenk, Felix Nickel, Thomas Fleming, David Sprinzak, Carolin Mogler, Thomas Korff, Adrian T. Billeter, Beat P. Müller-Stich, Mauricio Berriel Diaz, Tilman Borggrefe, Stephan Herzig, Maria Rohm, Juan Rodriguez-Vita, and Andreas Fischer. Endothelial notch1 signaling in white adipose tissue promotes cancer cachexia. Nature Cancer, 4:1544-1560, Sep 2023. URL: https://doi.org/10.1038/s43018-023-00622-y, doi:10.1038/s43018-023-00622-y. This article has 26 citations and is from a highest quality peer-reviewed journal.
(taylor2023endothelialnotch1signaling pages 11-12): Jacqueline Taylor, Leonie Uhl, Iris Moll, Sana Safatul Hasan, Lena Wiedmann, Jakob Morgenstern, Benedetto Daniele Giaimo, Tobias Friedrich, Elisenda Alsina-Sanchis, Francesca De Angelis Rigotti, Ronja Mülfarth, Sarah Kaltenbach, Darius Schenk, Felix Nickel, Thomas Fleming, David Sprinzak, Carolin Mogler, Thomas Korff, Adrian T. Billeter, Beat P. Müller-Stich, Mauricio Berriel Diaz, Tilman Borggrefe, Stephan Herzig, Maria Rohm, Juan Rodriguez-Vita, and Andreas Fischer. Endothelial notch1 signaling in white adipose tissue promotes cancer cachexia. Nature Cancer, 4:1544-1560, Sep 2023. URL: https://doi.org/10.1038/s43018-023-00622-y, doi:10.1038/s43018-023-00622-y. This article has 26 citations and is from a highest quality peer-reviewed journal.
(taylor2023endothelialnotch1signaling pages 5-6): Jacqueline Taylor, Leonie Uhl, Iris Moll, Sana Safatul Hasan, Lena Wiedmann, Jakob Morgenstern, Benedetto Daniele Giaimo, Tobias Friedrich, Elisenda Alsina-Sanchis, Francesca De Angelis Rigotti, Ronja Mülfarth, Sarah Kaltenbach, Darius Schenk, Felix Nickel, Thomas Fleming, David Sprinzak, Carolin Mogler, Thomas Korff, Adrian T. Billeter, Beat P. Müller-Stich, Mauricio Berriel Diaz, Tilman Borggrefe, Stephan Herzig, Maria Rohm, Juan Rodriguez-Vita, and Andreas Fischer. Endothelial notch1 signaling in white adipose tissue promotes cancer cachexia. Nature Cancer, 4:1544-1560, Sep 2023. URL: https://doi.org/10.1038/s43018-023-00622-y, doi:10.1038/s43018-023-00622-y. This article has 26 citations and is from a highest quality peer-reviewed journal.
(melvin2024thehistonemethyltransferase pages 1-2): William J. Melvin, Tyler M. Bauer, Kevin D. Mangum, Christopher O. Audu, James Shadiow, Emily C. Barrett, Amrita D. Joshi, Jadie Y. Moon, Rachel Bogle, Purba Mazumder, Sonya J. Wolf, Steven L. Kunke, Johann E. Gudjonsson, Frank M. Davis, and Katherine A. Gallagher. The histone methyltransferase mixed-lineage-leukemia-1 drives t cell phenotype via notch signaling in diabetic tissue repair. JCI Insight, Aug 2024. URL: https://doi.org/10.1172/jci.insight.179012, doi:10.1172/jci.insight.179012. This article has 5 citations and is from a domain leading peer-reviewed journal.
(freitas2024notch1blockadeby pages 7-10): Juliano Tiburcio de Freitas, Varsha Thakur, Kathryn M. LaPorte, Vijay S. Thakur, Brian Flores, Valentina Caicedo, Chioma G. E. Ajaegbu, Giuseppe Ingrasci, Zoe M. Lipman, Keman Zhang, Hong Qiu, Thomas R. Malek, and Barbara Bedogni. Notch1 blockade by a novel, selective anti-notch1 neutralizing antibody improves immunotherapy efficacy in melanoma by promoting an inflamed tme. Journal of Experimental & Clinical Cancer Research : CR, Nov 2024. URL: https://doi.org/10.1186/s13046-024-03214-5, doi:10.1186/s13046-024-03214-5. This article has 4 citations.
(freitas2024notch1blockadeby pages 5-7): Juliano Tiburcio de Freitas, Varsha Thakur, Kathryn M. LaPorte, Vijay S. Thakur, Brian Flores, Valentina Caicedo, Chioma G. E. Ajaegbu, Giuseppe Ingrasci, Zoe M. Lipman, Keman Zhang, Hong Qiu, Thomas R. Malek, and Barbara Bedogni. Notch1 blockade by a novel, selective anti-notch1 neutralizing antibody improves immunotherapy efficacy in melanoma by promoting an inflamed tme. Journal of Experimental & Clinical Cancer Research : CR, Nov 2024. URL: https://doi.org/10.1186/s13046-024-03214-5, doi:10.1186/s13046-024-03214-5. This article has 4 citations.
(freitas2024notch1blockadeby pages 10-12): Juliano Tiburcio de Freitas, Varsha Thakur, Kathryn M. LaPorte, Vijay S. Thakur, Brian Flores, Valentina Caicedo, Chioma G. E. Ajaegbu, Giuseppe Ingrasci, Zoe M. Lipman, Keman Zhang, Hong Qiu, Thomas R. Malek, and Barbara Bedogni. Notch1 blockade by a novel, selective anti-notch1 neutralizing antibody improves immunotherapy efficacy in melanoma by promoting an inflamed tme. Journal of Experimental & Clinical Cancer Research : CR, Nov 2024. URL: https://doi.org/10.1186/s13046-024-03214-5, doi:10.1186/s13046-024-03214-5. This article has 4 citations.
(ke2024deltalike4 pages 11-11): Xingrao Ke, Sheng Xia, Wei Yu, Sherry Mabry, Qi Fu, Heather L. Menden, Venkatesh Sampath, and Robert H. Lane. Delta like 4 regulates cerebrovascular development and endothelial integrity via dll4‐notch‐cldn5 pathway and is vulnerable to neonatal hyperoxia. The Journal of Physiology, 602:2265-2285, Apr 2024. URL: https://doi.org/10.1113/jp285716, doi:10.1113/jp285716. This article has 8 citations.
(peng2023roleofthe pages 1-2): Xiafeng Peng, Shixin Wang, Hongwu Chen, and Minglong Chen. Role of the notch1 signaling pathway in ischemic heart disease (review). International journal of molecular medicine, Feb 2023. URL: https://doi.org/10.3892/ijmm.2023.5230, doi:10.3892/ijmm.2023.5230. This article has 26 citations and is from a peer-reviewed journal.

Citations

melvin2024thehistonemethyltransferase pages 1-2
czerwonka2023modulationofnotch pages 1-3
medina2023newtricksfor pages 2-4
sanlidag2025molecularandtissuelevel pages 19-22
bray2025modesofnotch pages 27-33
lv2024evolutionandfunction pages 2-4
sen2023theintricatenotch pages 1-2
wang2024mechanismofnotch pages 3-5
feng2024thestructuraland pages 21-25
fernandezchacon2023incongruencebetweentranscriptional pages 5-6
fernandezchacon2023incongruencebetweentranscriptional pages 7-8
fernandezchacon2023incongruencebetweentranscriptional pages 4-5
peng2023roleofthe pages 1-2
https://doi.org/10.1038/s44161-023-00272-4
https://doi.org/10.1113/jp285716
https://doi.org/10.1186/s12974-024-03246-w
https://doi.org/10.1038/s43018-023-00622-y
https://doi.org/10.1172/jci.insight.179012
https://doi.org/10.3390/cancers15184563
https://doi.org/10.1016/j.tips.2023.09.011
https://doi.org/10.1186/s13046-024-03214-5
https://doi.org/10.1038/s41580-025-00835-2,
https://doi.org/10.3390/cancers15184563,
https://doi.org/10.3390/ijms25063322,
https://doi.org/10.1021/acsptsci.2c00239,
https://doi.org/10.3390/biom14040480,
https://doi.org/10.1016/j.tips.2023.09.011,
https://doi.org/10.1038/s44161-023-00272-4,
https://doi.org/10.1113/jp285716,
https://doi.org/10.1186/s12974-024-03246-w,
https://doi.org/10.1038/s43018-023-00622-y,
https://doi.org/10.1172/jci.insight.179012,
https://doi.org/10.1186/s13046-024-03214-5,
https://doi.org/10.3892/ijmm.2023.5230,

Deep Research Openai

(Notch1-deep-research-openai.md)

provider: openai
model: o3-deep-research-2025-06-26
cached: false
start_time: '2026-03-20T00:35:47.451004'
end_time: '2026-03-20T00:43:40.321730'
duration_seconds: 472.87
template_file: templates/gene_research_go_focused.md
template_variables:
organism: mouse
gene_id: Notch1
gene_symbol: Notch1
uniprot_accession: Q01705
protein_description: 'RecName: Full=Neurogenic locus notch homolog protein 1; Short=Notch
1; AltName: Full=Motch A {ECO:0000303|PubMed:8440332}; AltName: Full=mT14; AltName:
Full=p300; Contains: RecName: Full=Notch 1 extracellular truncation {ECO:0000303|PubMed:10882062};
Short=NEXT {ECO:0000303|PubMed:10882062}; Contains: RecName: Full=Notch 1 intracellular
domain; Short=NICD; Flags: Precursor;'
gene_info: Name=Notch1; Synonyms=Motch {ECO:0000303|PubMed:8440332};
organism_full: Mus musculus (Mouse).
protein_family: Belongs to the NOTCH family. .
protein_domains: Ankyrin_rpt. (IPR002110); Ankyrin_rpt-contain_sf. (IPR036770);
EGF. (IPR000742); EGF-like_Ca-bd_dom. (IPR001881); EGF-like_CS. (IPR013032)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
temperature: 0.1
top_p: 1.0
citation_count: 98

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q01705
Protein Description: RecName: Full=Neurogenic locus notch homolog protein 1; Short=Notch 1; AltName: Full=Motch A {ECO:0000303|PubMed:8440332}; AltName: Full=mT14; AltName: Full=p300; Contains: RecName: Full=Notch 1 extracellular truncation {ECO:0000303|PubMed:10882062}; Short=NEXT {ECO:0000303|PubMed:10882062}; Contains: RecName: Full=Notch 1 intracellular domain; Short=NICD; Flags: Precursor;
Gene Information: Name=Notch1; Synonyms=Motch {ECO:0000303|PubMed:8440332};
Organism (full): Mus musculus (Mouse).
Protein Family: Belongs to the NOTCH family. .
Key Domains: Ankyrin_rpt. (IPR002110); Ankyrin_rpt-contain_sf. (IPR036770); EGF. (IPR000742); EGF-like_Ca-bd_dom. (IPR001881); EGF-like_CS. (IPR013032)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "Notch1" matches the protein description above
Verify the organism is correct: Mus musculus (Mouse).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene Notch1 (gene ID: Notch1, UniProt: Q01705) in mouse.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Output

Notch1 (Mus musculus) – Function and Biological Roles

Introduction and Key Concepts

Notch1 (Neurogenic locus notch homolog 1) is a single-pass transmembrane receptor in the mouse, encoded by the Notch1 gene (UniProt Q01705). It belongs to the highly conserved Notch family of receptors (Notch1–4 in mammals) that mediate cell–cell communication and cell fate decisions (www.nature.com) (www.nature.com). Notch1 was originally identified by homology to Drosophila Notch (a “neurogenic” gene controlling nervous system development) and shares the fundamental role of regulating how cells differentiate during development and homeostasis (www.nature.com). In essence, Notch1 functions as a ligand-activated signaling receptor: when activated by neighboring cells, it directly influences gene transcription in the nucleus, thereby altering cell behavior. This pathway is crucial for many developmental processes and continues to operate throughout the lifespan, with roles in maintaining adult tissue structure and responding to injury (www.nature.com). Consistent with its broad importance, Notch signaling (and Notch1 in particular) has been linked to numerous human diseases, including developmental disorders and cancers (www.nature.com).

Structure and Processing: The Notch1 protein is produced as a large precursor (~2530 amino acids) that undergoes proteolytic processing and contains several defined domains important for its function. The extracellular region of mouse Notch1 features 36 EGF-like repeats (epidermal growth factor–like domains) which facilitate ligand binding (pmc.ncbi.nlm.nih.gov). Within these repeats, a specific segment (around EGF repeats 11–12) is critical for recognizing Notch ligands (such as Delta-like and Jagged family proteins) (pmc.ncbi.nlm.nih.gov). Adjacent to the EGF repeats is the negative regulatory region (NRR), composed of three cysteine-rich LIN-12/Notch repeats (LNRs) and a heterodimerization (HD) domain (pmc.ncbi.nlm.nih.gov). In the Golgi apparatus, the nascent Notch1 precursor is cleaved at the HD domain by a furin-like convertase (this is called the S1 cleavage), separating the protein into an N-terminal extracellular subunit and a C-terminal transmembrane subunit that remain non-covalently associated (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This processing yields the mature heterodimeric Notch1 receptor that is transported to the cell surface (pmc.ncbi.nlm.nih.gov). The LNR–HD region keeps the receptor in an autoinhibited conformation, preventing signaling in the absence of ligand (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Notch1 is activated through direct cell–cell contact. When a Notch ligand (e.g. DLL1, DLL4, JAG1, or JAG2 on a neighboring cell) binds to the Notch1 extracellular domain, it induces a conformational change and “pulling” force that exposes the receptor’s cleavage site in the HD domain (pmc.ncbi.nlm.nih.gov). This leads to the second proteolytic cut (the S2 cleavage) by ADAM-family metalloproteases at the cell surface (pmc.ncbi.nlm.nih.gov). After this ligand-triggered S2 cleavage, the remaining membrane-tethered fragment of Notch1 – called NEXT (Notch extracellular truncation) – is rapidly cleaved within its transmembrane segment by the γ-secretase complex (S3 cleavage) (pmc.ncbi.nlm.nih.gov). The γ-secretase enzyme (a multi-subunit protease complex including Presenilin) releases the Notch1 intracellular domain (NICD) from the membrane (pmc.ncbi.nlm.nih.gov). This NICD is the key effector of Notch signaling: it translocates from the cytoplasm into the nucleus to regulate gene expression (pmc.ncbi.nlm.nih.gov). The NICD contains several functional domains: an RBPJ association module (RAM) near its N-terminus, seven ankyrin repeats (ANK) that serve as protein–protein interaction surfaces, two nuclear localization sequences (NLS) flanking the ANK region (ensuring NICD enters the nucleus), and a C-terminal PEST domain rich in proline, glutamic acid, serine, threonine (pmc.ncbi.nlm.nih.gov). The PEST motif carries degradation signals that target NICD for ubiquitin-mediated proteasomal turnover, thereby limiting the duration of Notch1 signaling (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Notch1’s overall architecture is shared by other Notch receptors, with Notch2–4 having similar domain organization and differing mostly in the number of EGF repeats and length of their PEST regions (pmc.ncbi.nlm.nih.gov).

Activation Mechanism and Signaling Pathway

Once liberated by γ-secretase, the Notch1 intracellular domain (NICD) acts as a transcriptional regulator. Canonical Notch signaling involves NICD partnering with a DNA-binding protein of the CSL family (also known as RBPJ in mammals, CBF1/Su(H)/Lag-1 in other species) (www.nature.com) (pmc.ncbi.nlm.nih.gov). In the absence of NICD, RBPJ/CSL is bound to target gene promoters along with corepressor proteins and histone deacetylases, keeping those target genes silenced (pmc.ncbi.nlm.nih.gov). When NICD enters the nucleus, it directly binds to RBPJ/CSL, via the RAM and ankyrin domains, and converts it into a transcriptional activator complex (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). NICD binding displaces the pre-bound corepressors and allows recruitment of coactivator proteins – most importantly, a Mastermind-like (MAML) protein, which bridges NICD and CSL and helps recruit the transcriptional machinery (pmc.ncbi.nlm.nih.gov). The assembled NICD–CSL–MAML complex drives expression of Notch target genes (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). A classic family of direct Notch targets are the Hairy/Enhancer of Split (HES) genes and their relatives the HEY genes, which encode transcriptional repressors that in turn modulate cell differentiation programs (pmc.ncbi.nlm.nih.gov). Thus, the primary outcome of Notch1 activation is changes in gene expression in the signal-receiving cell, typically leading to context-dependent effects like cell fate specification or inhibition of differentiation. Notch signaling is unusual in that the receptor itself (NICD fragment) becomes a part of the nuclear transcription factor complex, a mechanism often described as “signal transduction by proteolysis.” This directness bypasses second messengers and allows immediate transcriptional response to cell–cell interactions (www.nature.com). Importantly, Notch signaling is highly context-dependent – the same signal can have different outcomes depending on the cell type and the network of other signals and transcription factors present (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

The Notch pathway is conserved across metazoans and generally operates at short range, requiring cells to be in direct contact (pmc.ncbi.nlm.nih.gov). Mammals have five canonical Notch ligands (Delta-like 1, 3, 4 and Jagged-1, 2), which are themselves transmembrane proteins presented on adjacent cells (pmc.ncbi.nlm.nih.gov). Notch1–ligand binding is a unidirectional signaling event: the cell expressing the ligand acts as the “signaling” cell, and the cell expressing Notch1 receives the signal. Notch1 activation typically influences binary cell fate decisions – for example, helping one cell adopt a primary fate while its neighbors adopt an alternative fate, a process famously described as lateral inhibition in neurogenesis (pmc.ncbi.nlm.nih.gov). Notch1 can also mediate inductive signaling, where a steady Notch signal drives neighboring cells into a particular differentiated state. The specificity of action is partly achieved by the fact that Notch1’s influence is limited to the nucleus of the cell that produces NICD (there is no diffusion of NICD to other cells), and by the localized nature of ligand–receptor contact (often within epithelial cell junctions or niche microenvironments). After NICD initiates target gene transcription, its activity is attenuated by phosphorylation and ubiquitylation (primarily via the E3 ubiquitin ligase FBXW7 acting on the PEST domain), causing NICD degradation (pmc.ncbi.nlm.nih.gov). This built-in negative feedback ensures Notch1 signals are transient unless continually stimulated by ligand. Notch1 signaling can also be modulated by glycosylation of its EGF repeats (mediated by enzymes like Fringe), which alters ligand binding affinity and receptor activation (pmc.ncbi.nlm.nih.gov).

Recent insights: While the canonical CSL-dependent pathway is the best-understood mode of Notch1 action, studies show that Notch1 has additional non-canonical roles and regulatory modes. For instance, Notch1 and its ligands can interact within the same cell (“cis-interactions”) to inhibit signaling. In a 2024 study, Thambyrajah et al. demonstrated that in embryonic hematopoietic stem cells, Jagged1 ligands expressed on the same cell surface bind Notch1 in cis and prevent its activation, thereby preserving the stem cell fate (pmc.ncbi.nlm.nih.gov). If Notch1 in these cells is forcibly activated (bypassing cis-inhibition), the stem cells prematurely differentiate, indicating that Notch1 inactivity is required to maintain the stem cell state in that context (pmc.ncbi.nlm.nih.gov). This cis-inhibition mechanism highlights how cells can autonomously modulate Notch1 signaling strength by co-expressing ligands, adding a layer of control beyond external ligand availability. Another frontier in Notch1 biology is its transcription-independent functions. A 2023 study reported a form of “Notch1 cortical signaling” in which the Notch1 protein at the cell membrane (particularly the transmembrane domain and remaining juxtamembrane portions after NICD release) helps organize the cortical actin cytoskeleton and cell–cell junctions (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). White et al. (2023) found that Notch1 at epithelial adherens junctions interacts with an effector protein FAM83H and stabilizes E-cadherin-based cell adhesion, which in turn restrains EGFR signaling and excessive cell proliferation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Notably, this structural role required the presence of the Notch1 transmembrane segment (TMD) but not the NICD, suggesting it operates independently of gene transcription. Such non-canonical functions appear specialized (observed in mammary epithelial architectures and previously in endothelial cells (pmc.ncbi.nlm.nih.gov)) but reveal that Notch1 receptors can influence cell architecture and signaling at the cortex in addition to their classical nuclear role. These discoveries underscore that Notch1 is a versatile signaling module, with ongoing research uncovering new modes of action.

Biological Functions in Development and Homeostasis

Developmental roles: Notch1 is a master regulator of cell fate during embryonic development. Through iterative cell–cell signaling events, Notch1 helps pattern tissues and coordinate differentiation. In general, Notch1 activation tends to maintain an undifferentiated state or progenitor character in cells that receive the signal, thereby postponing or redirecting their differentiation. For example, in the nervous system, Notch1 signaling in neural progenitor cells inhibits neuronal differentiation, ensuring that not all cells convert into neurons at once. This mechanism – initially discovered from the neurogenic phenotype of Notch mutants in flies – is conserved in mammals and is critical for balancing neural stem cell maintenance with neuron production (www.nature.com). Loss of Notch activity in neural precursors leads to premature neuronal differentiation and depletion of the progenitor pool, whereas excessive Notch1 can block neurons from forming. Notch1 also plays repeated roles at later stages of neurodevelopment, influencing gliogenesis and synaptic patterning (often through induction of Hes/Hey genes that suppress proneural factors). Because of these roles, Notch1 is required for proper brain development and has been implicated in neurodevelopmental disorders when dysregulated (www.nature.com).

In the hematopoietic and immune system, Notch1 provides a famous example of a binary cell-fate switch. Notch1 signaling is essential for T-cell lineage commitment in the thymus. Experimental studies showed that if Notch1 is disabled in hematopoietic progenitor cells, those progenitors fail to become T cells and instead default to the B-cell lineage – even when they reside in the thymic environment (pmc.ncbi.nlm.nih.gov). In a landmark 2001 study, Radtke and colleagues demonstrated that Notch1–deficient common lymphoid precursors adopt a B cell fate in the thymus, whereas normally the thymus (via Notch-Delta signals) instructs them to become T cells (pmc.ncbi.nlm.nih.gov). Thus, Notch1 serves as a pivotal switch that directs lymphoid precursors towards the T cell program and away from the B cell program. Consistently, Delta-like ligands (especially DLL4) presented by thymic epithelial cells activate Notch1 on immigrant progenitors to trigger the T-cell developmental pathway. Beyond T cells, Notch1 (and related receptors) also influence other blood cell lineages and the formation of hematopoietic stem cells. During embryogenesis, Notch1 is required for the emergence of definitive hematopoietic stem cells from hemogenic endothelium in the aorta-gonad-mesonephros region (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). If Notch signaling is blocked at that stage, fewer HSCs are produced. In the adult bone marrow, Notch signals (from niche cells) continue to support HSC maintenance and may bias differentiation outcomes for lymphocytes and other lineages, although redundancy with other Notch receptors exists.

Notch1 is indispensable for proper organogenesis and tissue patterning. Mice lacking functional Notch1 die in mid-gestation, reflecting widespread developmental failures (www.nature.com). Notch1-null or Notch1 signal–deficient embryos display defects in somite segmentation (leading to irregular formation of the vertebral column segments) and in vascular development (www.nature.com). Notch1, together with DLL1 and DLL4, is crucial for the formation of the embryonic vasculature: it helps specify arterial endothelial cell identity and coordinate angiogenic sprouting. For instance, in developing blood vessels, cells with higher Notch1 activity adopt an arterial fate while suppressing venous differentiation, and Notch1-DLL4 interactions between endothelial tip and stalk cells refine the pattern of new vessel branching. Notch1 is also involved in the development of the heart (cardiac outflow tract and valves), pancreas, kidneys, and many other structures by modulating the differentiation of progenitors in those tissues. In each context, Notch1 often acts reiteratively: for example, controlling the proliferation of a progenitor pool, then later influencing the choice of specific cell subtypes that arise. Many of these roles have been defined by conditional knockout studies in mice. In the intestinal epithelium, Notch1 and Notch2 signals maintain the balance between absorptive enterocytes and secretory cells (goblet and others) – Notch activation promotes the absorptive cell fate and prevents secretory differentiation. Accordingly, inhibiting Notch (with γ-secretase inhibitors) in adult mice causes a rapid increase in goblet cells in the gut and loss of proliferative crypt progenitors, explaining why diarrhea is a side effect of systemic Notch blockade (pmc.ncbi.nlm.nih.gov). Notch1 signaling similarly maintains stem or progenitor states in the skin, inner ear, lung airways, and other renewing tissues, while coordinating proper differentiation timing. As Bray and Bigas (2025) note, Notch signaling often has “iterative roles” during development – first controlling the state of a progenitor, then later the fate of its progeny – and these roles can continue into adulthood in tissue maintenance and repair (www.nature.com). For example, Notch1 activity persists in adult neural stem cell niches (subventricular zone and hippocampus), where it restrains differentiation and promotes stem cell self-renewal, contributing to ongoing neurogenesis in a regulated manner (www.nature.com). In summary, Notch1’s primary biological function is to act as a context-dependent cell fate regulator: by transmitting local cell–cell signals into changes in gene expression, it shapes developmental patterning and ensures the proper balance between progenitors and differentiated cells in many tissues (pmc.ncbi.nlm.nih.gov) (www.nature.com).

Homeostasis and regeneration: Notch1’s influence extends beyond embryonic development into adult tissue homeostasis. Many adult stem cell systems exploit Notch signaling to control differentiation. We have mentioned the intestine and bone marrow as examples; similarly, in the epidermis, Notch1 promotes differentiation of keratinocytes. When Notch1 is active in a basal skin cell, it drives that cell to exit the stem cell compartment and differentiate into a spinous/intermediate cell, helping form the stratified layers. If Notch1 is lost in skin progenitors, those cells can expand excessively and fail to differentiate properly (www.nature.com). This role of Notch1 in inducing differentiation in skin (and thus restraining unchecked growth) is one reason that Notch1 is considered a tumor suppressor in the epidermis – Notch1-deficient skin can develop epidermal cancers (squamous cell carcinomas) due to accumulation of undifferentiated, proliferative cells (www.nature.com). In other contexts, Notch1 can act to support proliferation: for example, Notch signaling is involved in liver regeneration and cardiac injury responses, where it may help reactive progenitor cells expand or transform. The outcome depends on how the Notch1 targets interface with other pathways (e.g. Notch1 crosstalks with Wnt, TGF-β, and hypoxia pathways in various stem cell niches (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov)). Overall, Notch1 provides a means for cells in a community (tissue) to communicate and coordinate behavior, maintaining tissue architecture. This is vividly illustrated by the recent finding that Notch1 at cell junctions strengthens adhesion: in a confluent epithelial layer, Notch1’s presence at the cortex helps cells sense confluency and suppresses further growth (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In summary, from embryogenesis through adulthood, Notch1 plays a “gate-keeper” role in cell fate and differentiation, ensuring the right cells form at the right time and place, and that stem cell pools are neither prematurely exhausted nor overgrown. When this regulation goes awry, developmental defects or diseases can result.

Notch1 in Disease Contexts and Therapeutic Developments

Given its central role in regulating cell proliferation and differentiation, it is not surprising that NOTCH1 is involved in many diseases. Aberrant Notch1 signaling – either excessive or deficient – can contribute to oncogenesis, developmental syndromes, and other pathologies. Notch1 is somewhat unusual in that it can function as an oncogene in some tissues and a tumor suppressor in others (pmc.ncbi.nlm.nih.gov) (www.nature.com).

Oncogenic Notch1: The clearest example of Notch1 as an oncogenic driver is in T-cell acute lymphoblastic leukemia (T-ALL). NOTCH1 was first linked to human T-ALL in the early 1990s, and subsequent genomic studies revealed that more than 50% of T-ALL patients have somatic activating mutations in the NOTCH1 gene (pmc.ncbi.nlm.nih.gov). These mutations typically occur either in the HD domain (extracellular heterodimerization region) or in the C-terminal PEST domain of Notch1 (pmc.ncbi.nlm.nih.gov). HD domain mutations (e.g. small deletions or amino-acid substitutions) destabilize the autoinhibited conformation, essentially making the receptor prone to ligand-independent activation (pmc.ncbi.nlm.nih.gov). PEST domain mutations remove the degron signals, prolonging the NICD’s half-life in the nucleus (pmc.ncbi.nlm.nih.gov). Both types of mutations lead to excessive Notch1 signaling in T-cell progenitors. This drives leukemia by altering transcription of genes that control cell growth and metabolism – for example, Notch1 directly upregulates MYC and other oncogenic programs in T-ALL cells (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In mouse models, forced activation of Notch1 in hematopoietic stem cells or thymocytes is sufficient to induce T-cell leukemias (pmc.ncbi.nlm.nih.gov). The clinical relevance is significant: NOTCH1 status is being explored as a prognostic marker in T-ALL, and components of Notch signaling are targets for therapy (see below). Notch1 is also mutated or overactivated in certain solid tumors. For instance, about 10–15% of human non-small cell lung carcinomas (especially lung adenocarcinoma) have mutations in Notch pathway genes, sometimes including NOTCH1. Notch1 activation is linked to poor differentiation and stem-like tumor cell phenotype in some solid cancers such as triple-negative breast cancer and pancreatic ductal carcinoma (pmc.ncbi.nlm.nih.gov). On the other hand, in some tumors Notch1 acts as a tumor suppressor: frequent loss-of-function mutations in NOTCH1 are found in squamous cell carcinomas of the skin, esophagus, and head and neck (www.nature.com), suggesting that when Notch1’s prodifferentiation signal is removed, cells become prone to malignant transformation. Indeed, a study in mouse skin showed that Notch1 deletion led to spontaneous basal cell carcinomas, whereas activating Notch1 caused those cells to exit the cell cycle via differentiation (www.nature.com). This dichotomy exemplifies the context-dependent nature of Notch1 – promoting cancer in settings like T cells (where it sustains an undifferentiated, proliferative state) but suppressing cancer in settings like stratified epithelia (where it is needed to induce differentiation of potential cancer-initiating cells). Beyond cancer, germline mutations in Notch pathway components can cause developmental disorders. NOTCH1 germline mutations in humans have been associated with congenital heart defects, such as bicuspid aortic valve and left ventricular outflow tract malformations (pmc.ncbi.nlm.nih.gov). In these cases, heterozygous loss of Notch1 impairs valve formation and can lead to early-onset calcification of valves (pmc.ncbi.nlm.nih.gov). (Mutations in the ligand JAG1 or in NOTCH2 cause Alagille syndrome, a complex developmental disease affecting the liver, heart, and other organs (pmc.ncbi.nlm.nih.gov) – highlighting again that balanced Notch signaling is vital for normal organ development.)

Therapeutic targeting of Notch1: The prominent role of Notch1 in diseases like T-ALL has motivated efforts to develop Notch pathway inhibitors. The simplest way to block Notch signaling is to prevent NICD production via γ-secretase inhibitors (GSIs), since γ-secretase is required for S3 cleavage of all Notch receptors. In fact, one of the first clinical trials (launched in 2006) for Notch-related therapy used a GSI (MK-0752) in patients with refractory T-ALL (pmc.ncbi.nlm.nih.gov). The drug did achieve a reduction in leukemia burden in some cases (one T-ALL patient had ~45% tumor mass reduction in 4 weeks), but unfortunately the trial had to be halted due to dose-limiting toxicity – namely, severe gastrointestinal side effects (secretory diarrhea) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This toxicity was anticipated from animal studies: GSIs cause an overproduction of goblet cells in the intestines by blocking Notch1/2, disrupting gut homeostasis. The GSI trial outcome underscored a key challenge: Notch1 is so important in normal physiology that systemic inhibition leads to mechanism-related side effects (pmc.ncbi.nlm.nih.gov). Since then, researchers have pursued more selective strategies to inhibit Notch1 in cancer while sparing other tissues. One approach has been to develop monoclonal antibodies against specific Notch receptors or ligands. Brontictuzumab is a humanized antibody that binds the negative regulatory region of NOTCH1, stabilizing the autoinhibited conformation and preventing ligand activation. In a Phase I study (initiated 2013) of brontictuzumab in patients with advanced solid tumors, there were signs of anti-tumor activity: 2 out of 48 patients achieved partial tumor responses and 4 others had stable disease for ≥6 months, particularly in tumors like adenoid cystic carcinoma that are known to often have aberrant Notch activation (pmc.ncbi.nlm.nih.gov). Notably, adenoid cystic carcinomas with activating NOTCH1 mutations responded, suggesting target engagement (pmc.ncbi.nlm.nih.gov). However, even with this receptor-specific blockade, toxicities were observed – including grade 3 diarrhea and fatigue in some patients, which were dose-limiting (pmc.ncbi.nlm.nih.gov). These events reflect on-target effects of Notch1 inhibition in normal gut and perhaps other tissues. Other Notch-targeting agents have been tested, such as antibodies against Notch2/3 (e.g. tarextumab) and ligand blockers or decoys, with mixed results and sometimes unexpected pro-tumor effects in certain contexts (since Notch can also suppress tumors). There are also inhibitors of the Notch transcription complex under investigation (e.g. small molecules inhibiting RBPJ–NICD interaction or MAML function) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov), which might offer another route to dial down Notch1-driven gene expression. None of these therapies have yet achieved regulatory approval, due in part to the narrow therapeutic window.

Interestingly, one area where Notch1 status is being leveraged is cancer immunotherapy. Emerging evidence suggests that tumors harboring Notch pathway mutations (often loss-of-function) may respond differently to immune checkpoint blockade. Notch-inactivating mutations can lead to a less differentiated, more antigenic tumor cell phenotype and a pro-inflammatory microenvironment – for example, via increased T cell infiltration or higher expression of immune genes (pmc.ncbi.nlm.nih.gov). A recent clinical study in 2023 found that NSCLC patients with NOTCH1 mutations had significantly better outcomes on PD-1/PD-L1 inhibitor therapy than those with wild-type Notch1 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Specifically, NOTCH1-mutant lung cancer patients showed higher tumor mutational burden and achieved superior overall survival under checkpoint blockade (median overall survival was longer, and on multivariate analysis Notch1 mutation was associated with a hazard ratio ~0.4 for death) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This suggests that loss of Notch1 signaling in a tumor might increase immune visibility (perhaps by upregulating neoantigen expression or interferon pathways), making them more susceptible to immunotherapy. While this finding needs further validation, it points to NOTCH1 mutation as a potential biomarker for immunotherapy response in certain cancers. More broadly, it exemplifies how deepening our understanding of Notch1’s role in tumor biology could inform personalized treatment strategies – either by directly targeting the pathway or by exploiting its downstream effects on tumor–immune interactions.

Conclusion: Notch1 is a fundamental signaling protein that ties together cell-to-cell communication with gene regulation. Through its ligand-induced proteolysis mechanism, Notch1 directly converts external signals at the cell membrane into changes in transcriptional programs in the nucleus. It controls critical decisions in cell fate, proliferation, and differentiation in a context-dependent manner. Modern research (2023–2024) continues to reveal new facets of Notch1 biology – from cis-inhibitory loops that fine-tune stem cell signals (pmc.ncbi.nlm.nih.gov), to non-traditional roles in strengthening cell junctions and controlling cell polarity (pmc.ncbi.nlm.nih.gov). These insights expand our view of how Notch1 functions beyond the classical paradigm. Clinically, Notch1 stands as a double-edged sword: its dysregulation can lead to severe diseases, yet it is a challenging therapeutic target due to its importance in normal physiology. Ongoing work in developmental biology, structural biochemistry, and clinical oncology is converging to unravel how to modulate Notch1 safely and effectively. By learning how Notch1’s “molecular decisions” are made and modulated, scientists hope to design interventions that can, for example, shut down a Notch1-driven leukemia or stimulate regenerative healing in tissues, without collateral damage. Notch1 thus remains a focus of intense research as both a paradigm of cell signaling and a key node in human health and disease (pmc.ncbi.nlm.nih.gov) (www.nature.com).

References: (Publication dates and URLs are provided in citations throughout the text)

Citations

AnnotationURLCitation(end_index=519, start_index=379, title='Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1 | Nature', type='url_citation', url='https://www.nature.com/articles/35016111#:~:text=The%20Notch%20genes%20encode%20single,11%7D.%20Not%20all%20observations')
AnnotationURLCitation(end_index=679, start_index=520, title='Modes of Notch signalling in development and disease | Nature Reviews Molecular Cell Biology', type='url_citation', url='https://www.nature.com/articles/s41580-025-00835-2#:~:text=Many%20different%20animal%20developmental%20and,that%20it%20has%20many%20diverse')
AnnotationURLCitation(end_index=1073, start_index=914, title='Modes of Notch signalling in development and disease | Nature Reviews Molecular Cell Biology', type='url_citation', url='https://www.nature.com/articles/s41580-025-00835-2#:~:text=Many%20different%20animal%20developmental%20and,that%20it%20has%20many%20diverse')
AnnotationURLCitation(end_index=1613, start_index=1454, title='Modes of Notch signalling in development and disease | Nature Reviews Molecular Cell Biology', type='url_citation', url='https://www.nature.com/articles/s41580-025-00835-2#:~:text=Many%20different%20animal%20developmental%20and,that%20it%20has%20many%20diverse')
AnnotationURLCitation(end_index=1941, start_index=1786, title='Modes of Notch signalling in development and disease | Nature Reviews Molecular Cell Biology', type='url_citation', url='https://www.nature.com/articles/s41580-025-00835-2#:~:text=state%20of%20progenitor%20cells%20but,was%20uncovered%2C%20and%20it%20became')
AnnotationURLCitation(end_index=2457, start_index=2300, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=The%20extracellular%20domain%20%28N,domain%20are%20involved%20in%20ligand')
AnnotationURLCitation(end_index=2774, start_index=2617, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=The%20extracellular%20domain%20%28N,domain%20are%20involved%20in%20ligand')
AnnotationURLCitation(end_index=3070, start_index=2946, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=binding,for%20the%20stability%20of%20the')
AnnotationURLCitation(end_index=3516, start_index=3359, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=apparatus%2C%20NOTCH%20receptors%20are%20cleaved,secretase.%20The%20NOTCH')
AnnotationURLCitation(end_index=3650, start_index=3517, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=then%20experience%20S3%20cleavage%2C%20changing,2')
AnnotationURLCitation(end_index=3913, start_index=3756, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=apparatus%2C%20NOTCH%20receptors%20are%20cleaved,secretase.%20The%20NOTCH')
AnnotationURLCitation(end_index=4196, start_index=4036, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=NOTCH%20receptors%20are%20resistant%20to,NEXT%20can%20be%20further%20cleaved')
AnnotationURLCitation(end_index=4334, start_index=4197, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=S2%20cleavage%20is%20the%20only,58%7D.%20Once%20bound')
AnnotationURLCitation(end_index=4788, start_index=4628, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=NOTCH%20receptors%20are%20resistant%20to,NEXT%20can%20be%20further%20cleaved')
AnnotationURLCitation(end_index=5061, start_index=4901, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=NOTCH%20receptors%20are%20resistant%20to,NEXT%20can%20be%20further%20cleaved')
AnnotationURLCitation(end_index=5442, start_index=5309, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=then%20experience%20S3%20cleavage%2C%20changing,2')
AnnotationURLCitation(end_index=5726, start_index=5593, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=then%20experience%20S3%20cleavage%2C%20changing,2')
AnnotationURLCitation(end_index=5991, start_index=5858, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=then%20experience%20S3%20cleavage%2C%20changing,2')
AnnotationURLCitation(end_index=6521, start_index=6365, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=Located%20after%20the%20membrane,like%20repeats%2C%20the%20glycosylation')
AnnotationURLCitation(end_index=6852, start_index=6678, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=the%20nucleus%2C%20and%20seven%20ankyrin,is%20controlled%20by%20constitutive%20endocytosis')
AnnotationURLCitation(end_index=6981, start_index=6853, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=domains,4%20have%20similar%20structures%20to')
AnnotationURLCitation(end_index=7354, start_index=7181, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=contain%20degradation%20signals%20and%20are,appreciable%20amount%20of%20NOTCH%20receptors')
AnnotationURLCitation(end_index=7827, start_index=7680, title='Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1 | Nature', type='url_citation', url='https://www.nature.com/articles/35016111#:~:text=emerge%20for%20the%20Notch%20signalling,associated%20with%20a%20single%20point')
AnnotationURLCitation(end_index=7992, start_index=7828, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=match%20at%20L1990%20which%20contains,inhibitor%20of%20MAML1%2C%20inhibits%20the')
AnnotationURLCitation(end_index=8313, start_index=8155, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=In%20the%20traditional%20model%20of,targeting%20MAML%20are%20under%20study')
AnnotationURLCitation(end_index=8628, start_index=8470, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=In%20the%20traditional%20model%20of,targeting%20MAML%20are%20under%20study')
AnnotationURLCitation(end_index=8793, start_index=8629, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=match%20at%20L1990%20which%20contains,inhibitor%20of%20MAML1%2C%20inhibits%20the')
AnnotationURLCitation(end_index=9179, start_index=9021, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=In%20the%20traditional%20model%20of,targeting%20MAML%20are%20under%20study')
AnnotationURLCitation(end_index=9425, start_index=9261, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=match%20at%20L1990%20which%20contains,inhibitor%20of%20MAML1%2C%20inhibits%20the')
AnnotationURLCitation(end_index=9584, start_index=9426, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=In%20the%20traditional%20model%20of,targeting%20MAML%20are%20under%20study')
AnnotationURLCitation(end_index=9895, start_index=9806, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=co,23')
AnnotationURLCitation(end_index=10573, start_index=10433, title='Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1 | Nature', type='url_citation', url='https://www.nature.com/articles/35016111#:~:text=The%20Notch%20genes%20encode%20single,11%7D.%20Not%20all%20observations')
AnnotationURLCitation(end_index=10926, start_index=10776, title='Notch signaling pathway: architecture, disease, and therapeutics - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/35332121/#:~:text=the%20transcription%20of%20target%20genes,Collectively%2C%20the%20NOTCH')
AnnotationURLCitation(end_index=11099, start_index=10927, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=development%20and%20homeostasis%20of%20multiple,with%20new%20perspectives%20to%20inspire')
AnnotationURLCitation(end_index=11338, start_index=11234, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=three%20cleavages,42')
AnnotationURLCitation(end_index=11616, start_index=11496, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=Humans%20and%20mice%20have%20five,50')
AnnotationURLCitation(end_index=12186, start_index=12031, title='Notch 1–Deficient Common Lymphoid Precursors Adopt a B Cell Fate in the Thymus - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2193487/#:~:text=Notch%20proteins%20have%20been%20shown,family%20members%20in%20T%20cell')
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AnnotationURLCitation(end_index=14112, start_index=13975, title='Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10882055/#:~:text=inconsistent,clusters%20of%20the%20embryonic%20aorta')
AnnotationURLCitation(end_index=14492, start_index=14329, title='Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10882055/#:~:text=uncover%20that%20the%20HSC%20phenotype,clusters%20of%20the%20embryonic%20aorta')
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AnnotationURLCitation(end_index=22821, start_index=22673, title='Notch signaling pathway: architecture, disease, and therapeutics - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8948217/#:~:text=patients%20with%20T,in%20preclinical%20and%20clinical%20settings')
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AnnotationURLCitation(end_index=28119, start_index=28030, title='Modes of Notch signalling in development and disease | Nature Reviews Molecular Cell Biology', type='url_citation', url='https://www.nature.com/articles/s41580-025-00835-2#:~:text=135,Cancer')
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AnnotationURLCitation(end_index=38155, start_index=38027, title='NOTCH1 Mutations Predict Superior Outcomes of Immune Checkpoint Blockade in Non-Small Cell Lung Cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10710100/#:~:text=NOTCH1%20is%20frequently%20mutated%20in,ICB')
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AnnotationURLCitation(end_index=41490, start_index=41335, title='Modes of Notch signalling in development and disease | Nature Reviews Molecular Cell Biology', type='url_citation', url='https://www.nature.com/articles/s41580-025-00835-2#:~:text=state%20of%20progenitor%20cells%20but,was%20uncovered%2C%20and%20it%20became')

Bioreason Rl Review

(Notch1-bioreason-rl-review.md)

BioReason-Pro RL Review: Notch1 (mouse)

Source: Notch1-deep-research-bioreason-rl.md

Correctness: 4/5
Completeness: 4/5

Functional Summary Review

The BioReason functional summary is largely accurate:

A single-pass cell-surface receptor that uses a long calcium-stabilized EGF repeat array to sense extracellular cues and trigger intramembrane signaling. Upon ligand engagement and endocytic activation, a built-in regulatory switch releases the intracellular tail, which then assembles transcriptional effector complexes via ankyrin repeats to reprogram gene expression. This signaling cascade governs binary fate decisions and timing of differentiation by coupling extracellular recognition to intracellular transcriptional control at the plasma membrane.

This correctly describes: (1) the EGF repeat extracellular domain with calcium stabilization, (2) the proteolytic activation mechanism (intramembrane signaling), (3) the release of the intracellular domain (NICD), (4) the ankyrin repeat-mediated assembly of transcriptional complexes, and (5) the role in cell fate determination (GO:0001708). The curated review confirms Notch1 as "the canonical mouse Notch receptor" with roles in "cell-fate decisions during embryogenesis and tissue homeostasis."

The mention of "endocytic activation" is slightly misleading -- endocytosis by the ligand-presenting (signal-sending) cell provides the pulling force, but the Notch-bearing cell undergoes proteolytic cleavage at the membrane. The summary could be read as suggesting the Notch receptor itself is endocytosed for activation, which is not the primary mechanism.

A minor inaccuracy: the primary molecular function is described as "protein binding" (GO:0005515), which is too generic. The curated review identifies more specific functions including GO:0005112 (Notch binding), GO:0038023 (signaling receptor activity), and the transcriptional coactivator role. BioReason does not explicitly name the RBPJ/CSL transcription factor partnership in the summary, though the thinking trace does.

Comparison with interpro2go:

The curated review has six GO_REF:0000002 annotations: GO:0005509 (calcium ion binding), GO:0006355 (regulation of DNA-templated transcription), GO:0030154 (cell differentiation), GO:0038023 (signaling receptor activity), GO:0042981 (regulation of apoptotic process), and GO:0050793 (regulation of developmental process). BioReason's functional summary captures most of these conceptually (calcium stabilization, transcriptional regulation, cell fate/differentiation, receptor signaling) but misses the apoptotic connection. BioReason adds substantial value in explaining the proteolytic activation mechanism and the NOD/NODP regulatory switch, which interpro2go cannot convey.

Notes on thinking trace

The trace provides excellent analysis of the domain architecture, correctly interpreting the EGF repeat array, the NOD/NODP negative regulatory region, and the ankyrin repeat transcriptional scaffold. The mechanistic model of force-dependent activation and intramembrane proteolysis is accurate. The mention of Delta/Serrate/Jagged ligands and CSL/RBPJ complexes shows good biological context.

📄 View Raw YAML

id: Q01705
gene_symbol: Notch1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:10090
  label: Mus musculus
description: Notch1 is the canonical mouse Notch receptor, a single-pass transmembrane protein that mediates juxtacrine cell-cell signaling. Ligand binding by DLL/JAG family proteins triggers ADAM and gamma-secretase cleavage, releasing the Notch intracellular domain (NICD), which enters the nucleus and forms an RBPJ/MAML transcriptional coactivator complex to activate target genes. In mouse, Notch1 has central roles in cell-fate decisions during embryogenesis and tissue homeostasis, with especially strong evidence for cardiovascular development, neurogenesis/gliogenesis, hematopoietic stem cell regulation, angiogenesis, and inhibition of myogenic differentiation.
alternative_products:
  - name: '1'
    id: Q01705-1
  - name: '2'
    id: Q01705-2
    sequence_note: VSP_001402, VSP_001403, VSP_001404
  - name: '3'
    id: Q01705-3
    sequence_note: VSP_043064
  - name: '4'
    id: Q01705-4
    sequence_note: VSP_043065
existing_annotations:
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex.'
      action: ACCEPT
      reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x).
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007411
      label: axon guidance
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'The PANTHER IBA axon-guidance annotation appears to come from the broad PTHR45836 family, which includes both Notch receptors and canonical SLIT axon-guidance ligands.'
      action: REMOVE
      reason: Notch1 is a Notch receptor subfamily member, whereas axon guidance is a primary SLIT-family function in the same broad PANTHER family. The PANTHER metadata and reviewed member table support treating this as a family-transfer artifact rather than a Notch1 core function.
      supported_by:
        - reference_id: file:interpro/panther/PTHR45836/PTHR45836-metadata.yaml
          supporting_text: PTHR45836 is named Notch and Slit guidance protein and includes both Notch signaling and axonal guidance descriptions.
        - reference_id: file:interpro/panther/PTHR45836/PTHR45836-entries.csv
          supporting_text: Reviewed members include mouse Notch1 in subfamily SF12 and mouse/human Slit proteins in separate SLIT subfamilies.
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'Notch1 is expressed at the cell surface where it functions as a receptor for trans-acting ligands on neighboring cells.'
      action: ACCEPT
      reason: Cell surface localization is essential for Notch1 receptor function. The extracellular domain (N(EC)) binds ligands at the cell surface, triggering the proteolytic cascade.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0043235
      label: receptor complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'Notch1 exists as a heterodimeric receptor complex formed by furin cleavage during maturation. The N(EC) and N(TM) fragments remain associated at the cell surface.'
      action: ACCEPT
      reason: Notch1 forms a heterodimeric complex after S1 furin cleavage in the Golgi. The extracellular and transmembrane fragments are non-covalently associated. This is well-documented in UniProt and structural studies.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0001525
      label: angiogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 plays a key role in angiogenesis by negatively regulating endothelial cell proliferation and migration. DLL4-Notch1 signaling controls tip/stalk cell selection during vascular development.'
      action: KEEP_AS_NON_CORE
      reason: While angiogenesis is a well-documented biological context for Notch1 function, it represents a tissue-specific outcome rather than the core molecular function. UniProt confirms Notch1 is involved in angiogenesis, negatively regulating endothelial cell proliferation.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0001701
      label: in utero embryonic development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in in utero embryonic development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0001947
      label: heart looping
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 is required for proper cardiac morphogenesis including heart looping during development.'
      action: KEEP_AS_NON_CORE
      reason: Heart looping is a specific developmental process. Notch1 mutations cause congenital heart defects (AOVD1), confirming cardiac development roles, but this is tissue-specific.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0002011
      label: morphogenesis of an epithelial sheet
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in morphogenesis of an epithelial sheet, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0002064
      label: epithelial cell development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in epithelial cell development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0002437
      label: inflammatory response to antigenic stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in inflammatory response to antigenic stimulus, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005509
      label: calcium ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: 'Notch1 contains multiple EGF-like domains that bind calcium ions, which are essential for proper domain folding and ligand binding.'
      action: ACCEPT
      reason: Calcium binding is a core molecular function of Notch1. The EGF-like calcium-binding domains (IPR001881) are essential for Notch1 structure and function. UniProt lists calcium ion binding in the domain annotations.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription.'
      action: ACCEPT
      reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Cytosol'
      action: ACCEPT
      reason: NICD released to cytosol before nuclear import.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: 'NICD forms a transcriptional activation complex with RBPJ and MAML to regulate target gene expression.'
      action: MODIFY
      reason: The broad transcription-regulation parent is correct but too general for Notch1. The supported biology is NICD/RBPJ/MAML-dependent positive regulation of canonical Notch target transcription.
      proposed_replacement_terms:
        - id: GO:0007221
          label: positive regulation of transcription of Notch receptor target
        - id: GO:0045893
          label: positive regulation of DNA-templated transcription
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0006959
      label: humoral immune response
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in humoral immune response, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex.'
      action: ACCEPT
      reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x).
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010001
      label: glial cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in glial cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010718
      label: positive regulation of epithelial to mesenchymal transition
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 promotes positive regulation of epithelial to mesenchymal transition.'
      action: KEEP_AS_NON_CORE
      reason: EMT regulation - context-dependent function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010720
      label: positive regulation of cell development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in positive regulation of cell development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0012505
      label: endomembrane system
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in endomembrane system, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'Notch1 is a type I transmembrane protein that localizes to various cellular membranes during its lifecycle.'
      action: MODIFY
      reason: Generic membrane is true but too broad for curation. Notch1 localization is better represented by the specific plasma membrane, Golgi membrane, endoplasmic reticulum membrane, and late endosome membrane annotations already present in this review.
      proposed_replacement_terms:
        - id: GO:0005886
          label: plasma membrane
        - id: GO:0000139
          label: Golgi membrane
        - id: GO:0005789
          label: endoplasmic reticulum membrane
        - id: GO:0031902
          label: late endosome membrane
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030154
      label: cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: 'Notch1 is a master regulator of cell-fate determination and differentiation across multiple tissue contexts.'
      action: ACCEPT
      reason: Cell differentiation regulation is a core biological role of Notch1 signaling. UniProt states Notch1 affects implementation of differentiation, proliferation and apoptotic programs.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030326
      label: embryonic limb morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in embryonic limb morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030513
      label: positive regulation of BMP signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 is involved in positive regulation of bmp signaling pathway.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030858
      label: positive regulation of epithelial cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in positive regulation of epithelial cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0031902
      label: late endosome membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: 'Non-activated Notch1 receptor is targeted for lysosomal degradation via the endosomal pathway.'
      action: ACCEPT
      reason: UniProt explicitly states late endosome membrane localization and notes that non-activated receptor is targeted for lysosomal degradation via the endosomal pathway.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0035850
      label: epithelial cell differentiation involved in kidney development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in epithelial cell differentiation involved in kidney development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0038023
      label: signaling receptor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: 'Notch1 functions as a signaling receptor that transduces cell-cell contact signals into transcriptional responses.'
      action: MODIFY
      reason: Signaling receptor activity is correct but too generic for Notch1, which is specifically a transmembrane receptor activated by membrane-bound ligands and regulated proteolysis.
      proposed_replacement_terms:
        - id: GO:0004888
          label: transmembrane signaling receptor activity
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0042981
      label: regulation of apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in regulation of apoptotic process, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045165
      label: cell fate commitment
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'cell fate commitment is consistent with canonical mouse Notch1 receptor biology.'
      action: ACCEPT
      reason: Falcon synthesis identifies the conserved Notch1 mechanism as ER/Golgi maturation, plasma-membrane ligand reception, regulated proteolysis, NICD nuclear entry, and CSL/RBPJ-MAML transcriptional activation.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0048589
      label: developmental growth
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in developmental growth, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0048608
      label: reproductive structure development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in reproductive structure development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0048844
      label: artery morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in artery morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0050793
      label: regulation of developmental process
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: 'Notch1 is a key regulator of developmental processes including cell fate determination.'
      action: ACCEPT
      reason: Developmental regulation is a well-established function of Notch1. UniProt notes roles in postimplantation development, mesoderm development, somite formation, and neurogenesis.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0070986
      label: left/right axis specification
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 annotation to left/right axis specification.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0072012
      label: glomerulus vasculature development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in glomerulus vasculature development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0072080
      label: nephron tubule development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in nephron tubule development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:2000136
      label: regulation of cell proliferation involved in heart morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Notch1 has evidence for involvement in regulation of cell proliferation involved in heart morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17210915
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21102556
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22258620
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:38891776
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:8749394
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 can negatively regulate certain genes through target gene specificity and crosstalk with repressive mechanisms.'
      action: KEEP_AS_NON_CORE
      reason: While Notch1 primarily activates transcription, it can also lead to repression of certain targets depending on context. This is a secondary regulatory outcome.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0001554
      label: luteolysis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'The imported luteolysis annotation lacks gene-specific positive support in the local evidence for mouse Notch1.'
      action: UNDECIDED
      reason: Luteolysis is a specialized reproductive process and the available Falcon/UniProt context does not substantiate a specific Notch1 role beyond the imported electronic annotation. Leave undecided pending direct reproductive-context evidence.
  - term:
      id: GO:0001669
      label: acrosomal vesicle
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'The imported acrosomal vesicle annotation lacks direct mouse Notch1 localization support in the local evidence.'
      action: REMOVE
      reason: Notch1 has well-supported membrane, endosomal, and nuclear NICD localizations, but no local evidence links mouse Notch1 to acrosomal vesicle localization or sperm acrosome biology. The imported automated localization should be removed rather than retained as undecided.
  - term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 promotes epithelial to mesenchymal transition.'
      action: KEEP_AS_NON_CORE
      reason: EMT regulation - context-dependent function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0002052
      label: positive regulation of neuroblast proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 promotes neural progenitor/stem cell proliferation and maintains the undifferentiated state.'
      action: KEEP_AS_NON_CORE
      reason: Notch1 maintains neural stem cells and regulates neurogenesis, but this is a tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0002193
      label: MAML1-RBP-Jkappa- ICN1 complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'MAML1-RBP-Jkappa-ICN1 complex'
      action: ACCEPT
      reason: Core transcription activation complex.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003151
      label: outflow tract morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 annotation to outflow tract morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003180
      label: aortic valve morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 is essential for aortic valve development. Notch1 mutations cause aortic valve disease (AOVD1).'
      action: KEEP_AS_NON_CORE
      reason: Strongly supported by mouse genetics - Notch1 mutations cause bicuspid aortic valve and calcific aortic valve disease (OMIM:109730). This is a key developmental phenotype but tissue-specific.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003184
      label: pulmonary valve morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 regulates pulmonary valve development. Mouse Notch1 mutations cause pulmonary valve abnormalities.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac valve development - tissue-specific developmental function supported by mouse genetics.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003192
      label: mitral valve formation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 regulates mitral valve formation.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003264
      label: regulation of cardioblast proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 regulates cardioblast proliferation during heart development.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003713
      label: transcription coactivator activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'NICD functions as a transcriptional coactivator by converting RBPJ from a repressor to an activator.'
      action: ACCEPT
      reason: Transcription coactivator activity is a core molecular function of NICD. It recruits MAML and displaces corepressors from RBPJ.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0004888
      label: transmembrane signaling receptor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'Notch1 is a transmembrane receptor that transduces signals from cell-cell contact to transcriptional responses.'
      action: ACCEPT
      reason: This is the core molecular function of Notch1. It is a type I transmembrane receptor that signals via proteolytic processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007221
      label: positive regulation of transcription of Notch receptor target
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'Positive regulation of transcription of Notch receptor target'
      action: ACCEPT
      reason: Core downstream function of NICD.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007283
      label: spermatogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 annotation to spermatogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007507
      label: heart development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 regulates heart development.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'Notch1 is involved in positive regulation of cell population proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 is involved in negative regulation of cell population proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 is involved in positive regulation of gene expression.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010629
      label: negative regulation of gene expression
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 is involved in negative regulation of gene expression.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010667
      label: negative regulation of cardiac muscle cell apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 regulates negative regulation of cardiac muscle cell apoptotic process.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010812
      label: negative regulation of cell-substrate adhesion
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 is involved in negative regulation of cell-substrate adhesion.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0021515
      label: cell differentiation in spinal cord
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 is involved in cell differentiation in spinal cord.'
      action: KEEP_AS_NON_CORE
      reason: Neural development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0031100
      label: animal organ regeneration
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 annotation to animal organ regeneration.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0032496
      label: response to lipopolysaccharide
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 is involved in response to lipopolysaccharide.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0032966
      label: negative regulation of collagen biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 is involved in negative regulation of collagen biosynthetic process.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0035148
      label: tube formation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 annotation to tube formation.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0035924
      label: cellular response to vascular endothelial growth factor stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 regulates cellular response to vascular endothelial growth factor stimulus.'
      action: KEEP_AS_NON_CORE
      reason: Vascular development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0042127
      label: regulation of cell population proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 annotation to regulation of cell population proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0042246
      label: tissue regeneration
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 annotation to tissue regeneration.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 can form homodimers through its heterodimerization domain. Mutations in this domain cause T-ALL.'
      action: ACCEPT
      reason: Notch1 homodimerization is documented and has functional significance. The study shows leukemia-associated mutations fall into distinct mechanistic classes affecting the HD domain.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0043235
      label: receptor complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 exists as a heterodimeric receptor complex formed by furin cleavage during maturation. The N(EC) and N(TM) fragments remain associated at the cell surface.'
      action: ACCEPT
      reason: Notch1 forms a heterodimeric complex after S1 furin cleavage in the Golgi. The extracellular and transmembrane fragments are non-covalently associated. This is well-documented in UniProt and structural studies.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045603
      label: positive regulation of endothelial cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 regulates positive regulation of endothelial cell differentiation.'
      action: KEEP_AS_NON_CORE
      reason: Vascular development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045662
      label: negative regulation of myoblast differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 is involved in negative regulation of myoblast differentiation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045665
      label: negative regulation of neuron differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'Notch1 is involved in negative regulation of neuron differentiation via Notch-mediated lateral inhibition, a canonical function in the neuron-glia binary fate decision.'
      action: KEEP_AS_NON_CORE
      reason: Notch1-mediated effects on neuron differentiation are well-supported developmental outputs, but they are tissue-context consequences of the core juxtacrine receptor/NICD transcription mechanism rather than the core function itself.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045687
      label: positive regulation of glial cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 promotes glial cell differentiation via lateral inhibition, instructing multipotent progenitors toward glial fate.'
      action: KEEP_AS_NON_CORE
      reason: Glial differentiation is a supported neural-developmental output of Notch1 signaling, but it is a context-specific consequence rather than the core receptor/NICD transcription mechanism.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'NICD positively regulates transcription by forming a coactivator complex with RBPJ and MAML that displaces corepressors.'
      action: ACCEPT
      reason: Notch1 NICD functions as a transcriptional activator. The NICD-RBPJ-MAML complex recruits coactivators like p300 to activate target gene transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0046579
      label: positive regulation of Ras protein signal transduction
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 has been reported to crosstalk with Ras/MAPK signaling in certain cellular contexts.'
      action: KEEP_AS_NON_CORE
      reason: This represents crosstalk with other signaling pathways rather than the core Notch1 function. The canonical Notch pathway does not involve direct Ras activation, though downstream effects can influence Ras signaling.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0048708
      label: astrocyte differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 promotes astrocyte differentiation as part of gliogenesis, with Sox9 acting as critical downstream mediator.'
      action: KEEP_AS_NON_CORE
      reason: Astrocyte differentiation is a supported downstream neural-lineage outcome, but it is not the general core molecular or cellular function of Notch1.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0048709
      label: oligodendrocyte differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 regulates oligodendrocyte differentiation (inhibitory role - promotes astrocyte over oligodendrocyte fate).'
      action: KEEP_AS_NON_CORE
      reason: Oligodendrocyte differentiation is a neural-lineage output of Notch1 signaling and should be retained as non-core rather than as the defining receptor/NICD function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0051152
      label: positive regulation of smooth muscle cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 promotes vascular smooth muscle cell differentiation and is required for arterial smooth muscle development.'
      action: KEEP_AS_NON_CORE
      reason: Smooth muscle differentiation is a tissue-specific developmental outcome of Notch1 signaling rather than a core function. It represents one of many differentiation contexts where Notch1 plays a role.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060354
      label: negative regulation of cell adhesion molecule production
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 is involved in negative regulation of cell adhesion molecule production.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060412
      label: ventricular septum morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 annotation to ventricular septum morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0062043
      label: positive regulation of cardiac epithelial to mesenchymal transition
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 regulates positive regulation of cardiac epithelial to mesenchymal transition.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0070374
      label: positive regulation of ERK1 and ERK2 cascade
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 can promote ERK1/2 signaling in certain cellular contexts, representing pathway crosstalk.'
      action: KEEP_AS_NON_CORE
      reason: ERK cascade regulation is not part of canonical Notch signaling but may occur through indirect mechanisms or crosstalk in specific contexts.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0071228
      label: cellular response to tumor cell
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 has been implicated in tumor microenvironment responses.'
      action: KEEP_AS_NON_CORE
      reason: This is a specialized context-dependent role of Notch1 in cancer biology rather than a core function of the protein.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0071372
      label: cellular response to follicle-stimulating hormone stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'The imported cellular response to follicle-stimulating hormone stimulus annotation lacks gene-specific positive support in the local evidence for mouse Notch1.'
      action: UNDECIDED
      reason: The available Falcon/UniProt context does not substantiate a specific Notch1 response to FSH. Leave undecided pending direct reproductive-endocrine evidence.
  - term:
      id: GO:0090051
      label: negative regulation of cell migration involved in sprouting angiogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 regulates negative regulation of cell migration involved in sprouting angiogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Vascular development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0097150
      label: neuronal stem cell population maintenance
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 is involved in neuronal stem cell population maintenance.'
      action: KEEP_AS_NON_CORE
      reason: Neural development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:2000048
      label: negative regulation of cell-cell adhesion mediated by cadherin
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 is involved in negative regulation of cell-cell adhesion mediated by cadherin.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:2000737
      label: negative regulation of stem cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 is involved in negative regulation of stem cell differentiation.'
      action: KEEP_AS_NON_CORE
      reason: Stem cell regulation - context-dependent function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:2000811
      label: negative regulation of anoikis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 is involved in negative regulation of anoikis.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:2001027
      label: negative regulation of endothelial cell chemotaxis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'Notch1 regulates negative regulation of endothelial cell chemotaxis.'
      action: KEEP_AS_NON_CORE
      reason: Vascular development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 can negatively regulate certain genes through target gene specificity and crosstalk with repressive mechanisms.'
      action: KEEP_AS_NON_CORE
      reason: While Notch1 primarily activates transcription, it can also lead to repression of certain targets depending on context. This is a secondary regulatory outcome.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 promotes epithelial to mesenchymal transition.'
      action: KEEP_AS_NON_CORE
      reason: EMT regulation - context-dependent function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0002193
      label: MAML1-RBP-Jkappa- ICN1 complex
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'MAML1-RBP-Jkappa-ICN1 complex'
      action: ACCEPT
      reason: Core transcription activation complex.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003151
      label: outflow tract morphogenesis
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 annotation to outflow tract morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003180
      label: aortic valve morphogenesis
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 is essential for aortic valve development. Notch1 mutations cause aortic valve disease (AOVD1).'
      action: KEEP_AS_NON_CORE
      reason: Strongly supported by mouse genetics - Notch1 mutations cause bicuspid aortic valve and calcific aortic valve disease (OMIM:109730). This is a key developmental phenotype but tissue-specific.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003184
      label: pulmonary valve morphogenesis
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 regulates pulmonary valve development. Mouse Notch1 mutations cause pulmonary valve abnormalities.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac valve development - tissue-specific developmental function supported by mouse genetics.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003192
      label: mitral valve formation
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 regulates mitral valve formation.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003713
      label: transcription coactivator activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'NICD functions as a transcriptional coactivator by converting RBPJ from a repressor to an activator.'
      action: ACCEPT
      reason: Transcription coactivator activity is a core molecular function of NICD. It recruits MAML and displaces corepressors from RBPJ.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0004888
      label: transmembrane signaling receptor activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 is a transmembrane receptor that transduces signals from cell-cell contact to transcriptional responses.'
      action: ACCEPT
      reason: This is the core molecular function of Notch1. It is a type I transmembrane receptor that signals via proteolytic processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription.'
      action: ACCEPT
      reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex.'
      action: ACCEPT
      reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x).
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007507
      label: heart development
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 regulates heart development.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 is involved in positive regulation of cell population proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 is involved in negative regulation of cell population proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010629
      label: negative regulation of gene expression
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 is involved in negative regulation of gene expression.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010812
      label: negative regulation of cell-substrate adhesion
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 is involved in negative regulation of cell-substrate adhesion.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0035148
      label: tube formation
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 annotation to tube formation.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0035924
      label: cellular response to vascular endothelial growth factor stimulus
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 regulates cellular response to vascular endothelial growth factor stimulus.'
      action: KEEP_AS_NON_CORE
      reason: Vascular development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 can form homodimers through its heterodimerization domain. Mutations in this domain cause T-ALL.'
      action: ACCEPT
      reason: Notch1 homodimerization is documented and has functional significance. The study shows leukemia-associated mutations fall into distinct mechanistic classes affecting the HD domain.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045662
      label: negative regulation of myoblast differentiation
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 is involved in negative regulation of myoblast differentiation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'NICD positively regulates transcription by forming a coactivator complex with RBPJ and MAML that displaces corepressors.'
      action: ACCEPT
      reason: Notch1 NICD functions as a transcriptional activator. The NICD-RBPJ-MAML complex recruits coactivators like p300 to activate target gene transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0046579
      label: positive regulation of Ras protein signal transduction
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 has been reported to crosstalk with Ras/MAPK signaling in certain cellular contexts.'
      action: KEEP_AS_NON_CORE
      reason: This represents crosstalk with other signaling pathways rather than the core Notch1 function. The canonical Notch pathway does not involve direct Ras activation, though downstream effects can influence Ras signaling.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0051152
      label: positive regulation of smooth muscle cell differentiation
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 promotes vascular smooth muscle cell differentiation and is required for arterial smooth muscle development.'
      action: KEEP_AS_NON_CORE
      reason: Smooth muscle differentiation is a tissue-specific developmental outcome of Notch1 signaling rather than a core function. It represents one of many differentiation contexts where Notch1 plays a role.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060354
      label: negative regulation of cell adhesion molecule production
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 is involved in negative regulation of cell adhesion molecule production.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060412
      label: ventricular septum morphogenesis
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 annotation to ventricular septum morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0070374
      label: positive regulation of ERK1 and ERK2 cascade
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 can promote ERK1/2 signaling in certain cellular contexts, representing pathway crosstalk.'
      action: KEEP_AS_NON_CORE
      reason: ERK cascade regulation is not part of canonical Notch signaling but may occur through indirect mechanisms or crosstalk in specific contexts.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0071228
      label: cellular response to tumor cell
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 has been implicated in tumor microenvironment responses.'
      action: KEEP_AS_NON_CORE
      reason: This is a specialized context-dependent role of Notch1 in cancer biology rather than a core function of the protein.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0071372
      label: cellular response to follicle-stimulating hormone stimulus
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'The imported cellular response to follicle-stimulating hormone stimulus annotation lacks gene-specific positive support in the local evidence for mouse Notch1.'
      action: UNDECIDED
      reason: The available Falcon/UniProt context does not substantiate a specific Notch1 response to FSH. Leave undecided pending direct reproductive-endocrine evidence.
  - term:
      id: GO:0090051
      label: negative regulation of cell migration involved in sprouting angiogenesis
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 regulates negative regulation of cell migration involved in sprouting angiogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Vascular development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:2000048
      label: negative regulation of cell-cell adhesion mediated by cadherin
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 is involved in negative regulation of cell-cell adhesion mediated by cadherin.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:2000737
      label: negative regulation of stem cell differentiation
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 is involved in negative regulation of stem cell differentiation.'
      action: KEEP_AS_NON_CORE
      reason: Stem cell regulation - context-dependent function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:2000811
      label: negative regulation of anoikis
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 is involved in negative regulation of anoikis.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:2001027
      label: negative regulation of endothelial cell chemotaxis
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'Notch1 regulates negative regulation of endothelial cell chemotaxis.'
      action: KEEP_AS_NON_CORE
      reason: Vascular development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: IDA
    original_reference_id: PMID:26491108
    review:
      summary: 'Notch1 is involved in negative regulation of cell population proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: IMP
    original_reference_id: PMID:26491108
    review:
      summary: 'Notch1 is involved in negative regulation of cell population proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:2000137
      label: negative regulation of cell proliferation involved in heart morphogenesis
    evidence_type: IDA
    original_reference_id: PMID:26491108
    review:
      summary: 'Notch1 has evidence for involvement in negative regulation of cell proliferation involved in heart morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:2000137
      label: negative regulation of cell proliferation involved in heart morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:26491108
    review:
      summary: 'Notch1 has evidence for involvement in negative regulation of cell proliferation involved in heart morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:1990433
      label: CSL-Notch-Mastermind transcription factor complex
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: 'CSL-Notch-Mastermind transcription factor complex is consistent with canonical mouse Notch1 receptor biology.'
      action: ACCEPT
      reason: Falcon synthesis identifies the conserved Notch1 mechanism as ER/Golgi maturation, plasma-membrane ligand reception, regulated proteolysis, NICD nuclear entry, and CSL/RBPJ-MAML transcriptional activation.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0001669
      label: acrosomal vesicle
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'The imported acrosomal vesicle annotation lacks direct mouse Notch1 localization support in the local evidence.'
      action: REMOVE
      reason: Notch1 has well-supported membrane, endosomal, and nuclear NICD localizations, but no local evidence links mouse Notch1 to acrosomal vesicle localization or sperm acrosome biology. The orthology-imported localization should be removed rather than retained as undecided.
  - term:
      id: GO:0002052
      label: positive regulation of neuroblast proliferation
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 promotes neural progenitor/stem cell proliferation and maintains the undifferentiated state.'
      action: KEEP_AS_NON_CORE
      reason: Notch1 maintains neural stem cells and regulates neurogenesis, but this is a tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003264
      label: regulation of cardioblast proliferation
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 regulates cardioblast proliferation during heart development.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0004888
      label: transmembrane signaling receptor activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 is a transmembrane receptor that transduces signals from cell-cell contact to transcriptional responses.'
      action: ACCEPT
      reason: This is the core molecular function of Notch1. It is a type I transmembrane receptor that signals via proteolytic processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription.'
      action: ACCEPT
      reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex.'
      action: ACCEPT
      reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x).
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007221
      label: positive regulation of transcription of Notch receptor target
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Positive regulation of transcription of Notch receptor target'
      action: ACCEPT
      reason: Core downstream function of NICD.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007283
      label: spermatogenesis
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 annotation to spermatogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 is involved in positive regulation of gene expression.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010667
      label: negative regulation of cardiac muscle cell apoptotic process
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 regulates negative regulation of cardiac muscle cell apoptotic process.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0032966
      label: negative regulation of collagen biosynthetic process
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 is involved in negative regulation of collagen biosynthetic process.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0042127
      label: regulation of cell population proliferation
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 annotation to regulation of cell population proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045603
      label: positive regulation of endothelial cell differentiation
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 regulates positive regulation of endothelial cell differentiation.'
      action: KEEP_AS_NON_CORE
      reason: Vascular development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045665
      label: negative regulation of neuron differentiation
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 is involved in negative regulation of neuron differentiation via Notch-mediated lateral inhibition, a canonical function in the neuron-glia binary fate decision.'
      action: KEEP_AS_NON_CORE
      reason: Notch1-mediated effects on neuron differentiation are well-supported developmental outputs, but they are tissue-context consequences of the core juxtacrine receptor/NICD transcription mechanism rather than the core function itself.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045687
      label: positive regulation of glial cell differentiation
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 promotes glial cell differentiation via lateral inhibition, instructing multipotent progenitors toward glial fate.'
      action: KEEP_AS_NON_CORE
      reason: Glial differentiation is a supported neural-developmental output of Notch1 signaling, but it is a context-specific consequence rather than the core receptor/NICD transcription mechanism.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0048708
      label: astrocyte differentiation
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 promotes astrocyte differentiation as part of gliogenesis, with Sox9 acting as critical downstream mediator.'
      action: KEEP_AS_NON_CORE
      reason: Astrocyte differentiation is a supported downstream neural-lineage outcome, but it is not the general core molecular or cellular function of Notch1.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0062043
      label: positive regulation of cardiac epithelial to mesenchymal transition
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: 'Notch1 regulates positive regulation of cardiac epithelial to mesenchymal transition.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0098685
      label: Schaffer collateral - CA1 synapse
    evidence_type: IMP
    original_reference_id: PMID:21315255
    review:
      summary: 'Notch1 annotation to Schaffer collateral - CA1 synapse.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0098685
      label: Schaffer collateral - CA1 synapse
    evidence_type: IDA
    original_reference_id: PMID:21315255
    review:
      summary: 'Notch1 annotation to Schaffer collateral - CA1 synapse.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0098685
      label: Schaffer collateral - CA1 synapse
    evidence_type: IMP
    original_reference_id: PMID:26635527
    review:
      summary: 'Notch1 annotation to Schaffer collateral - CA1 synapse.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0098685
      label: Schaffer collateral - CA1 synapse
    evidence_type: IDA
    original_reference_id: PMID:26635527
    review:
      summary: 'Notch1 annotation to Schaffer collateral - CA1 synapse.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0098839
      label: postsynaptic density membrane
    evidence_type: IEP
    original_reference_id: PMID:21315255
    review:
      summary: 'Notch1 annotation to postsynaptic density membrane.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0098839
      label: postsynaptic density membrane
    evidence_type: IDA
    original_reference_id: PMID:21315255
    review:
      summary: 'Notch1 annotation to postsynaptic density membrane.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0098839
      label: postsynaptic density membrane
    evidence_type: IDA
    original_reference_id: PMID:26635527
    review:
      summary: 'Notch1 annotation to postsynaptic density membrane.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0098978
      label: glutamatergic synapse
    evidence_type: IMP
    original_reference_id: PMID:26635527
    review:
      summary: 'Notch1 annotation to glutamatergic synapse.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0098978
      label: glutamatergic synapse
    evidence_type: IDA
    original_reference_id: PMID:26635527
    review:
      summary: 'Notch1 annotation to glutamatergic synapse.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0099565
      label: chemical synaptic transmission, postsynaptic
    evidence_type: IMP
    original_reference_id: PMID:21315255
    review:
      summary: 'Notch1 annotation to chemical synaptic transmission, postsynaptic.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0099565
      label: chemical synaptic transmission, postsynaptic
    evidence_type: IDA
    original_reference_id: PMID:21315255
    review:
      summary: 'Notch1 annotation to chemical synaptic transmission, postsynaptic.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: 'Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex.'
      action: ACCEPT
      reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x).
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:14701881
    review:
      summary: 'Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex.'
      action: ACCEPT
      reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x).
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:20007915
    review:
      summary: 'Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex.'
      action: ACCEPT
      reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x).
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IGI
    original_reference_id: PMID:20890042
    review:
      summary: 'Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex.'
      action: ACCEPT
      reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x).
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0061344
      label: regulation of cell adhesion involved in heart morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:14701881
    review:
      summary: 'Notch1 regulates regulation of cell adhesion involved in heart morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0070168
      label: negative regulation of biomineral tissue development
    evidence_type: IMP
    original_reference_id: PMID:26491108
    review:
      summary: 'Notch1 is involved in negative regulation of biomineral tissue development.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:22110751
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010008
      label: endosome membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-9793875
    review:
      summary: 'Endosome membrane'
      action: ACCEPT
      reason: Notch1 trafficking.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010832
      label: negative regulation of myotube differentiation
    evidence_type: IMP
    original_reference_id: PMID:18299578
    review:
      summary: 'Notch1 is involved in negative regulation of myotube differentiation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0050768
      label: negative regulation of neurogenesis
    evidence_type: IMP
    original_reference_id: PMID:18299578
    review:
      summary: 'Notch1 is involved in negative regulation of neurogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Neural development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0071456
      label: cellular response to hypoxia
    evidence_type: IDA
    original_reference_id: PMID:18299578
    review:
      summary: 'Notch1 is involved in cellular response to hypoxia.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0140537
      label: transcription regulator activator activity
    evidence_type: IDA
    original_reference_id: PMID:18299578
    review:
      summary: 'Notch1 annotation to transcription regulator activator activity.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:20007915
    review:
      summary: 'Notch1 annotation to regulation of transcription by RNA polymerase II.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060379
      label: cardiac muscle cell myoblast differentiation
    evidence_type: IMP
    original_reference_id: PMID:20007915
    review:
      summary: 'Notch1 regulates cardiac muscle cell myoblast differentiation.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27719760
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18430783
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030163
      label: protein catabolic process
    evidence_type: IDA
    original_reference_id: PMID:28561022
    review:
      summary: 'Notch1 annotation to protein catabolic process.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28561022
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0006606
      label: protein import into nucleus
    evidence_type: IDA
    original_reference_id: PMID:28561022
    review:
      summary: 'Notch1 annotation to protein import into nucleus.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010467
      label: gene expression
    evidence_type: IDA
    original_reference_id: PMID:28561022
    review:
      summary: 'Notch1 annotation to gene expression.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0072538
      label: T-helper 17 type immune response
    evidence_type: IDA
    original_reference_id: PMID:28561022
    review:
      summary: 'Notch1 regulates t-helper 17 type immune response.'
      action: KEEP_AS_NON_CORE
      reason: T cell/immune development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0097400
      label: interleukin-17-mediated signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:28561022
    review:
      summary: 'Notch1 annotation to interleukin-17-mediated signaling pathway.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007221
      label: positive regulation of transcription of Notch receptor target
    evidence_type: IGI
    original_reference_id: PMID:12794108
    review:
      summary: 'Positive regulation of transcription of Notch receptor target'
      action: ACCEPT
      reason: Core downstream function of NICD.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007221
      label: positive regulation of transcription of Notch receptor target
    evidence_type: IGI
    original_reference_id: PMID:23160044
    review:
      summary: 'Positive regulation of transcription of Notch receptor target'
      action: ACCEPT
      reason: Core downstream function of NICD.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003713
      label: transcription coactivator activity
    evidence_type: IDA
    original_reference_id: PMID:17658278
    review:
      summary: 'NICD functions as a transcriptional coactivator by converting RBPJ from a repressor to an activator.'
      action: ACCEPT
      reason: Transcription coactivator activity is a core molecular function of NICD. It recruits MAML and displaces corepressors from RBPJ.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003713
      label: transcription coactivator activity
    evidence_type: IDA
    original_reference_id: PMID:9111338
    review:
      summary: 'NICD functions as a transcriptional coactivator by converting RBPJ from a repressor to an activator.'
      action: ACCEPT
      reason: Transcription coactivator activity is a core molecular function of NICD. It recruits MAML and displaces corepressors from RBPJ.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003713
      label: transcription coactivator activity
    evidence_type: IDA
    original_reference_id: PMID:17336907
    review:
      summary: 'NICD functions as a transcriptional coactivator by converting RBPJ from a repressor to an activator.'
      action: ACCEPT
      reason: Transcription coactivator activity is a core molecular function of NICD. It recruits MAML and displaces corepressors from RBPJ.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24667410
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0070168
      label: negative regulation of biomineral tissue development
    evidence_type: IDA
    original_reference_id: PMID:23583836
    review:
      summary: 'Notch1 is involved in negative regulation of biomineral tissue development.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:17336907
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0120163
      label: negative regulation of cold-induced thermogenesis
    evidence_type: IMP
    original_reference_id: PMID:25038826
    review:
      summary: 'Notch1 is involved in negative regulation of cold-induced thermogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003180
      label: aortic valve morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:26491108
    review:
      summary: 'Notch1 is essential for aortic valve development. Notch1 mutations cause aortic valve disease (AOVD1).'
      action: KEEP_AS_NON_CORE
      reason: Strongly supported by mouse genetics - Notch1 mutations cause bicuspid aortic valve and calcific aortic valve disease (OMIM:109730). This is a key developmental phenotype but tissue-specific.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003182
      label: coronary sinus valve morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:26491108
    review:
      summary: 'Notch1 regulates coronary sinus valve development.'
      action: KEEP_AS_NON_CORE
      reason: Highly specialized cardiac structure - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003184
      label: pulmonary valve morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:26491108
    review:
      summary: 'Notch1 regulates pulmonary valve development. Mouse Notch1 mutations cause pulmonary valve abnormalities.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac valve development - tissue-specific developmental function supported by mouse genetics.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003332
      label: negative regulation of extracellular matrix constituent secretion
    evidence_type: IMP
    original_reference_id: PMID:26491108
    review:
      summary: 'Notch1 negatively regulates ECM secretion in certain contexts.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:26491108
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010614
      label: negative regulation of cardiac muscle hypertrophy
    evidence_type: IMP
    original_reference_id: PMID:26491108
    review:
      summary: 'Notch1 regulates negative regulation of cardiac muscle hypertrophy.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060412
      label: ventricular septum morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:26491108
    review:
      summary: 'Notch1 annotation to ventricular septum morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:1902339
      label: positive regulation of apoptotic process involved in morphogenesis
    evidence_type: IDA
    original_reference_id: PMID:26491108
    review:
      summary: 'Notch1 is involved in positive regulation of apoptotic process involved in morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003180
      label: aortic valve morphogenesis
    evidence_type: IGI
    original_reference_id: PMID:27107132
    review:
      summary: 'Notch1 is essential for aortic valve development. Notch1 mutations cause aortic valve disease (AOVD1).'
      action: KEEP_AS_NON_CORE
      reason: Strongly supported by mouse genetics - Notch1 mutations cause bicuspid aortic valve and calcific aortic valve disease (OMIM:109730). This is a key developmental phenotype but tissue-specific.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003184
      label: pulmonary valve morphogenesis
    evidence_type: IGI
    original_reference_id: PMID:27107132
    review:
      summary: 'Notch1 regulates pulmonary valve development. Mouse Notch1 mutations cause pulmonary valve abnormalities.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac valve development - tissue-specific developmental function supported by mouse genetics.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003203
      label: endocardial cushion morphogenesis
    evidence_type: IGI
    original_reference_id: PMID:27107132
    review:
      summary: 'Notch1 is required for endocardial cushion development which gives rise to heart valves.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0048873
      label: homeostasis of number of cells within a tissue
    evidence_type: IGI
    original_reference_id: PMID:27107132
    review:
      summary: 'Notch1 annotation to homeostasis of number of cells within a tissue.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060412
      label: ventricular septum morphogenesis
    evidence_type: IGI
    original_reference_id: PMID:27107132
    review:
      summary: 'Notch1 annotation to ventricular septum morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003180
      label: aortic valve morphogenesis
    evidence_type: IGI
    original_reference_id: PMID:23583836
    review:
      summary: 'Notch1 is essential for aortic valve development. Notch1 mutations cause aortic valve disease (AOVD1).'
      action: KEEP_AS_NON_CORE
      reason: Strongly supported by mouse genetics - Notch1 mutations cause bicuspid aortic valve and calcific aortic valve disease (OMIM:109730). This is a key developmental phenotype but tissue-specific.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:23583836
    review:
      summary: 'The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription.'
      action: ACCEPT
      reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: IGI
    original_reference_id: PMID:23583836
    review:
      summary: 'Notch1 is involved in positive regulation of gene expression.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28089369
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28498977
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0048845
      label: venous blood vessel morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:18952909
    review:
      summary: 'Notch1 has evidence for involvement in venous blood vessel morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:1903849
      label: positive regulation of aorta morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:18952909
    review:
      summary: 'Notch1 has evidence for involvement in positive regulation of aorta morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010468
      label: regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:11076679
    review:
      summary: 'Notch1 has evidence for involvement in regulation of gene expression, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21191019
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045070
      label: positive regulation of viral genome replication
    evidence_type: IMP
    original_reference_id: PMID:21191019
    review:
      summary: 'Notch1 is involved in positive regulation of viral genome replication.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003197
      label: endocardial cushion development
    evidence_type: IMP
    original_reference_id: PMID:14701881
    review:
      summary: 'Notch1 has evidence for involvement in endocardial cushion development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21985982
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18676613
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24715457
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005912
      label: adherens junction
    evidence_type: IDA
    original_reference_id: PMID:24715457
    review:
      summary: 'Notch1 annotation to adherens junction.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0016324
      label: apical plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:24715457
    review:
      summary: 'Notch1 annotation to apical plasma membrane.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12050162
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:25535395
    review:
      summary: 'Notch1 annotation to regulation of transcription by RNA polymerase II.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: IMP
    original_reference_id: PMID:25535395
    review:
      summary: 'Notch1 is involved in negative regulation of cell population proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0042127
      label: regulation of cell population proliferation
    evidence_type: IGI
    original_reference_id: PMID:25535395
    review:
      summary: 'Notch1 annotation to regulation of cell population proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045607
      label: regulation of inner ear auditory receptor cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:25535395
    review:
      summary: 'Notch1 has evidence for involvement in regulation of inner ear auditory receptor cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045608
      label: negative regulation of inner ear auditory receptor cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:25535395
    review:
      summary: 'Notch1 has evidence for involvement in negative regulation of inner ear auditory receptor cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0090090
      label: negative regulation of canonical Wnt signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:25535395
    review:
      summary: 'Notch1 has evidence for involvement in negative regulation of canonical Wnt signaling pathway, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005112
      label: Notch binding
    evidence_type: IPI
    original_reference_id: PMID:24667410
    review:
      summary: 'Notch1 can bind other Notch family members, potentially in cis-inhibition or heterodimer formation.'
      action: ACCEPT
      reason: Notch receptors can interact with each other. The identical protein binding annotation (GO:0042802) already captures homodimerization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005783
      label: endoplasmic reticulum
    evidence_type: IDA
    original_reference_id: PMID:24667410
    review:
      summary: 'Endoplasmic reticulum'
      action: ACCEPT
      reason: Notch1 synthesis and maturation.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:24667410
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0008593
      label: regulation of Notch signaling pathway
    evidence_type: IGI
    original_reference_id: PMID:24667410
    review:
      summary: 'regulation of Notch signaling pathway is consistent with canonical mouse Notch1 receptor biology.'
      action: ACCEPT
      reason: Falcon synthesis identifies the conserved Notch1 mechanism as ER/Golgi maturation, plasma-membrane ligand reception, regulated proteolysis, NICD nuclear entry, and CSL/RBPJ-MAML transcriptional activation.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0031410
      label: cytoplasmic vesicle
    evidence_type: IDA
    original_reference_id: PMID:24667410
    review:
      summary: 'Notch1 annotation to cytoplasmic vesicle.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045747
      label: positive regulation of Notch signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:24667410
    review:
      summary: 'positive regulation of Notch signaling pathway is consistent with canonical mouse Notch1 receptor biology.'
      action: ACCEPT
      reason: Falcon synthesis identifies the conserved Notch1 mechanism as ER/Golgi maturation, plasma-membrane ligand reception, regulated proteolysis, NICD nuclear entry, and CSL/RBPJ-MAML transcriptional activation.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0071944
      label: cell periphery
    evidence_type: IDA
    original_reference_id: PMID:23284756
    review:
      summary: 'Notch1 annotation to cell periphery.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0043235
      label: receptor complex
    evidence_type: ISO
    original_reference_id: PMID:23382219
    review:
      summary: 'Notch1 exists as a heterodimeric receptor complex formed by furin cleavage during maturation. The N(EC) and N(TM) fragments remain associated at the cell surface.'
      action: ACCEPT
      reason: Notch1 forms a heterodimeric complex after S1 furin cleavage in the Golgi. The extracellular and transmembrane fragments are non-covalently associated. This is well-documented in UniProt and structural studies.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060271
      label: cilium assembly
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: 'Notch1 annotation to cilium assembly.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:1902263
      label: apoptotic process involved in embryonic digit morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:16245338
    review:
      summary: 'Notch1 has evidence for involvement in apoptotic process involved in embryonic digit morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0001726
      label: ruffle
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: 'Notch1 has evidence for involvement in ruffle, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005856
      label: cytoskeleton
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: 'Notch1 has evidence for involvement in cytoskeleton, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030027
      label: lamellipodium
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: 'Notch1 has evidence for involvement in lamellipodium, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: 'Notch1 is involved in negative regulation of cell population proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0035148
      label: tube formation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: 'Notch1 annotation to tube formation.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0035924
      label: cellular response to vascular endothelial growth factor stimulus
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: 'Notch1 regulates cellular response to vascular endothelial growth factor stimulus.'
      action: KEEP_AS_NON_CORE
      reason: Vascular development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0090051
      label: negative regulation of cell migration involved in sprouting angiogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: 'Notch1 regulates negative regulation of cell migration involved in sprouting angiogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Vascular development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:2001027
      label: negative regulation of endothelial cell chemotaxis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: 'Notch1 regulates negative regulation of endothelial cell chemotaxis.'
      action: KEEP_AS_NON_CORE
      reason: Vascular development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0035914
      label: skeletal muscle cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:22147266
    review:
      summary: 'Notch1 has evidence for involvement in skeletal muscle cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:17685488
    review:
      summary: 'The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription.'
      action: ACCEPT
      reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:14701881
    review:
      summary: 'Notch1 can negatively regulate certain genes through target gene specificity and crosstalk with repressive mechanisms.'
      action: KEEP_AS_NON_CORE
      reason: While Notch1 primarily activates transcription, it can also lead to repression of certain targets depending on context. This is a secondary regulatory outcome.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:16025100
    review:
      summary: 'Notch1 can negatively regulate certain genes through target gene specificity and crosstalk with repressive mechanisms.'
      action: KEEP_AS_NON_CORE
      reason: While Notch1 primarily activates transcription, it can also lead to repression of certain targets depending on context. This is a secondary regulatory outcome.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IMP
    original_reference_id: PMID:20007915
    review:
      summary: 'The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription.'
      action: ACCEPT
      reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:14701881
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:16025100
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:17303760
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:20007915
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003180
      label: aortic valve morphogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: 'Notch1 is essential for aortic valve development. Notch1 mutations cause aortic valve disease (AOVD1).'
      action: KEEP_AS_NON_CORE
      reason: Strongly supported by mouse genetics - Notch1 mutations cause bicuspid aortic valve and calcific aortic valve disease (OMIM:109730). This is a key developmental phenotype but tissue-specific.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003213
      label: cardiac right atrium morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:20007915
    review:
      summary: 'Notch1 regulates right atrium morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003241
      label: growth involved in heart morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:20007915
    review:
      summary: 'Notch1 regulates growth during cardiac morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0014031
      label: mesenchymal cell development
    evidence_type: IMP
    original_reference_id: PMID:17303760
    review:
      summary: 'Notch1 promotes mesenchymal cell development.'
      action: KEEP_AS_NON_CORE
      reason: EMT regulation - context-dependent function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030279
      label: negative regulation of ossification
    evidence_type: IMP
    original_reference_id: PMID:21493891
    review:
      summary: 'Notch1 is involved in negative regulation of ossification.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IMP
    original_reference_id: PMID:19695258
    review:
      summary: 'Notch1 is involved in negative regulation of dna-templated transcription.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:15107403
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0055008
      label: cardiac muscle tissue morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:20007915
    review:
      summary: 'Notch1 regulates cardiac muscle tissue morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060045
      label: positive regulation of cardiac muscle cell proliferation
    evidence_type: IMP
    original_reference_id: PMID:20007915
    review:
      summary: 'Notch1 regulates positive regulation of cardiac muscle cell proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060317
      label: cardiac epithelial to mesenchymal transition
    evidence_type: IMP
    original_reference_id: PMID:17303760
    review:
      summary: 'Notch1 regulates cardiac epithelial to mesenchymal transition.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060411
      label: cardiac septum morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:20007915
    review:
      summary: 'Notch1 regulates cardiac septum morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060842
      label: arterial endothelial cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:15107403
    review:
      summary: 'Notch1 regulates arterial endothelial cell differentiation.'
      action: KEEP_AS_NON_CORE
      reason: Vascular development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:20890042
    review:
      summary: 'Notch1 can negatively regulate certain genes through target gene specificity and crosstalk with repressive mechanisms.'
      action: KEEP_AS_NON_CORE
      reason: While Notch1 primarily activates transcription, it can also lead to repression of certain targets depending on context. This is a secondary regulatory outcome.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0001947
      label: heart looping
    evidence_type: IGI
    original_reference_id: PMID:12730124
    review:
      summary: 'Notch1 is required for proper cardiac morphogenesis including heart looping during development.'
      action: KEEP_AS_NON_CORE
      reason: Heart looping is a specific developmental process. Notch1 mutations cause congenital heart defects (AOVD1), confirming cardiac development roles, but this is tissue-specific.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003160
      label: endocardium morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:20890042
    review:
      summary: 'Notch1 regulates endocardium morphogenesis during heart development.'
      action: KEEP_AS_NON_CORE
      reason: Related to cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003162
      label: atrioventricular node development
    evidence_type: IMP
    original_reference_id: PMID:21266778
    review:
      summary: 'Notch1 is involved in development of cardiac conduction system components.'
      action: KEEP_AS_NON_CORE
      reason: Specialized cardiac developmental process.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003169
      label: coronary vein morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:21311046
    review:
      summary: 'Notch1 regulates coronary vessel development including vein morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac/vascular development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003181
      label: atrioventricular valve morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:14701881
    review:
      summary: 'Notch1 regulates AV valve development through endocardial cushion formation.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac valve development - tissue-specific developmental function supported by mouse studies.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003181
      label: atrioventricular valve morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:21266778
    review:
      summary: 'Notch1 regulates AV valve development through endocardial cushion formation.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac valve development - tissue-specific developmental function supported by mouse studies.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003198
      label: epithelial to mesenchymal transition involved in endocardial cushion formation
    evidence_type: IMP
    original_reference_id: PMID:14701881
    review:
      summary: 'Notch1 promotes EMT during endocardial cushion formation, essential for valve development.'
      action: KEEP_AS_NON_CORE
      reason: EMT in heart development is well-documented for Notch1. Tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003203
      label: endocardial cushion morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:14701881
    review:
      summary: 'Notch1 is required for endocardial cushion development which gives rise to heart valves.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003207
      label: cardiac chamber formation
    evidence_type: IMP
    original_reference_id: PMID:20890042
    review:
      summary: 'Notch1 regulates cardiac chamber formation during heart development.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003208
      label: cardiac ventricle morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:21311046
    review:
      summary: 'Notch1 regulates ventricular development.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003209
      label: cardiac atrium morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:20890042
    review:
      summary: 'Notch1 regulates atrial development.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003214
      label: cardiac left ventricle morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:20890042
    review:
      summary: 'Notch1 regulates left ventricle morphogenesis. Relevant to hypoplastic left heart syndrome.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003273
      label: cell migration involved in endocardial cushion formation
    evidence_type: IMP
    original_reference_id: PMID:20890042
    review:
      summary: 'Notch1 regulates cell migration during endocardial cushion formation.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003344
      label: pericardium morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:14701881
    review:
      summary: 'Notch1 regulates pericardium development.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003344
      label: pericardium morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:20890042
    review:
      summary: 'Notch1 regulates pericardium development.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003344
      label: pericardium morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:21311046
    review:
      summary: 'Notch1 regulates pericardium development.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010718
      label: positive regulation of epithelial to mesenchymal transition
    evidence_type: IMP
    original_reference_id: PMID:20890042
    review:
      summary: 'Notch1 promotes positive regulation of epithelial to mesenchymal transition.'
      action: KEEP_AS_NON_CORE
      reason: EMT regulation - context-dependent function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030334
      label: regulation of cell migration
    evidence_type: IMP
    original_reference_id: PMID:20890042
    review:
      summary: 'Notch1 annotation to regulation of cell migration.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030335
      label: positive regulation of cell migration
    evidence_type: IMP
    original_reference_id: PMID:20890042
    review:
      summary: 'Notch1 is involved in positive regulation of cell migration.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:21311046
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060038
      label: cardiac muscle cell proliferation
    evidence_type: IMP
    original_reference_id: PMID:21311046
    review:
      summary: 'Notch1 regulates cardiac muscle cell proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060843
      label: venous endothelial cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:20890042
    review:
      summary: 'Notch1 regulates venous endothelial cell differentiation.'
      action: KEEP_AS_NON_CORE
      reason: Vascular development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060948
      label: cardiac vascular smooth muscle cell development
    evidence_type: IMP
    original_reference_id: PMID:21311046
    review:
      summary: 'Notch1 regulates cardiac vascular smooth muscle cell development.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060956
      label: endocardial cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:20890042
    review:
      summary: 'Notch1 annotation to endocardial cell differentiation.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060979
      label: vasculogenesis involved in coronary vascular morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:21311046
    review:
      summary: 'Notch1 regulates vasculogenesis involved in coronary vascular morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060982
      label: coronary artery morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:21311046
    review:
      summary: 'Notch1 regulates coronary artery morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0061384
      label: heart trabecula morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:20890042
    review:
      summary: 'Notch1 regulates heart trabecula morphogenesis.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0070986
      label: left/right axis specification
    evidence_type: IGI
    original_reference_id: PMID:12730124
    review:
      summary: 'Notch1 annotation to left/right axis specification.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:1901201
      label: regulation of extracellular matrix assembly
    evidence_type: IMP
    original_reference_id: PMID:21311046
    review:
      summary: 'Notch1 annotation to regulation of extracellular matrix assembly.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:17336907
    review:
      summary: 'The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription.'
      action: ACCEPT
      reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:1901189
      label: positive regulation of ephrin receptor signaling pathway
    evidence_type: IC
    original_reference_id: PMID:17336907
    review:
      summary: 'Notch1 has evidence for involvement in positive regulation of ephrin receptor signaling pathway, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003157
      label: endocardium development
    evidence_type: IMP
    original_reference_id: PMID:17336907
    review:
      summary: 'Notch1 is essential for endocardium development and endocardial cell differentiation.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development is a well-established Notch1 function based on mouse disease genetics (AOVD1, AOS5), but represents tissue-specific developmental role.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003222
      label: ventricular trabecula myocardium morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:17336907
    review:
      summary: 'Notch1 regulates trabeculation of the ventricular myocardium.'
      action: KEEP_AS_NON_CORE
      reason: Cardiac development - tissue-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-4396387
    review:
      summary: 'Nucleoplasm'
      action: ACCEPT
      reason: NICD functions in nucleoplasm for transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-9667655
    review:
      summary: 'Nucleoplasm'
      action: ACCEPT
      reason: NICD functions in nucleoplasm for transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-9824206
    review:
      summary: 'Nucleoplasm'
      action: ACCEPT
      reason: NICD functions in nucleoplasm for transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-9824230
    review:
      summary: 'Nucleoplasm'
      action: ACCEPT
      reason: NICD functions in nucleoplasm for transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-9824231
    review:
      summary: 'Nucleoplasm'
      action: ACCEPT
      reason: NICD functions in nucleoplasm for transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-9824278
    review:
      summary: 'Nucleoplasm'
      action: ACCEPT
      reason: NICD functions in nucleoplasm for transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-2064853
    review:
      summary: 'Nucleoplasm'
      action: ACCEPT
      reason: NICD functions in nucleoplasm for transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-2064883
    review:
      summary: 'Nucleoplasm'
      action: ACCEPT
      reason: NICD functions in nucleoplasm for transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-2065560
    review:
      summary: 'Nucleoplasm'
      action: ACCEPT
      reason: NICD functions in nucleoplasm for transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-4396363
    review:
      summary: 'Nucleoplasm'
      action: ACCEPT
      reason: NICD functions in nucleoplasm for transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2067638
    review:
      summary: 'Cytosol'
      action: ACCEPT
      reason: NICD released to cytosol before nuclear import.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-209285
    review:
      summary: 'Cytosol'
      action: ACCEPT
      reason: NICD released to cytosol before nuclear import.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-2065902
    review:
      summary: 'Cytosol'
      action: ACCEPT
      reason: NICD released to cytosol before nuclear import.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IPI
    original_reference_id: PMID:17573339
    review:
      summary: 'Enzyme binding'
      action: ACCEPT
      reason: Notch1 binds enzymes involved in its processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IPI
    original_reference_id: PMID:18299578
    review:
      summary: 'Enzyme binding'
      action: ACCEPT
      reason: Notch1 binds enzymes involved in its processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:19245366
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0004857
      label: enzyme inhibitor activity
    evidence_type: IDA
    original_reference_id: PMID:17573339
    review:
      summary: 'The Notch1 ankyrin-repeat domain can inhibit factor inhibiting HIF (FIH) in vitro, but this is a context-specific biochemical interaction rather than the core Notch receptor function.'
      action: KEEP_AS_NON_CORE
      reason: PMID:17573339 reports that Notch ankyrin-repeat domains compete with HIF for FIH-dependent hydroxylation and proposes ARD proteins as natural FIH inhibitors. Retain the term as supported non-core biochemistry, distinct from canonical Notch ligand-receptor signaling and NICD transcriptional coactivation.
      supported_by:
        - reference_id: PMID:17573339
          supporting_text: ARD proteins were found to efficiently compete with HIF for FIH-dependent hydroxylation
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon synthesis identifies Notch1 core function as ligand-triggered receptor cleavage and NICD/CSL/MAML transcriptional signaling; FIH inhibition is peripheral.]'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:18299578
    review:
      summary: 'The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription.'
      action: ACCEPT
      reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:21419176
    review:
      summary: 'Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex.'
      action: ACCEPT
      reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x).
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0043086
      label: negative regulation of catalytic activity
    evidence_type: IDA
    original_reference_id: PMID:17573339
    review:
      summary: 'Notch1 is involved in negative regulation of catalytic activity.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2053938
    review:
      summary: 'Notch1 annotation to extracellular region.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2053963
    review:
      summary: 'Notch1 annotation to extracellular region.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2066712
    review:
      summary: 'Notch1 annotation to extracellular region.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2067638
    review:
      summary: 'Notch1 annotation to extracellular region.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2071906
    review:
      summary: 'Notch1 annotation to extracellular region.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2077477
    review:
      summary: 'Notch1 annotation to extracellular region.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2077479
    review:
      summary: 'Notch1 annotation to extracellular region.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-2065902
    review:
      summary: 'Notch1 annotation to extracellular region.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-209162
    review:
      summary: 'Notch1 annotation to extracellular region.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0000139
      label: Golgi membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2023158
    review:
      summary: 'Notch1 undergoes S1 cleavage by furin in the trans-Golgi network during maturation, converting the precursor into the functional heterodimer.'
      action: ACCEPT
      reason: Golgi membrane localization is part of the Notch1 biosynthetic pathway. UniProt states the precursor is proteolytically cleaved by furin-like convertase in the trans-Golgi network before reaching the plasma membrane.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0000139
      label: Golgi membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2032750
    review:
      summary: 'Notch1 undergoes S1 cleavage by furin in the trans-Golgi network during maturation, converting the precursor into the functional heterodimer.'
      action: ACCEPT
      reason: Golgi membrane localization is part of the Notch1 biosynthetic pathway. UniProt states the precursor is proteolytically cleaved by furin-like convertase in the trans-Golgi network before reaching the plasma membrane.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2023179
    review:
      summary: 'Notch1 is synthesized and begins its maturation in the ER membrane before trafficking to the Golgi.'
      action: ACCEPT
      reason: ER membrane localization is part of the Notch1 biosynthetic pathway. UniProt notes synthesis in the endoplasmic reticulum as an inactive form.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2032750
    review:
      summary: 'Notch1 is synthesized and begins its maturation in the ER membrane before trafficking to the Golgi.'
      action: ACCEPT
      reason: ER membrane localization is part of the Notch1 biosynthetic pathway. UniProt notes synthesis in the endoplasmic reticulum as an inactive form.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-9824249
    review:
      summary: 'Notch1 is synthesized and begins its maturation in the ER membrane before trafficking to the Golgi.'
      action: ACCEPT
      reason: ER membrane localization is part of the Notch1 biosynthetic pathway. UniProt notes synthesis in the endoplasmic reticulum as an inactive form.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-1986584
    review:
      summary: 'Notch1 is synthesized and begins its maturation in the ER membrane before trafficking to the Golgi.'
      action: ACCEPT
      reason: ER membrane localization is part of the Notch1 biosynthetic pathway. UniProt notes synthesis in the endoplasmic reticulum as an inactive form.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-209285
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-2063915
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-209162
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2053938
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15574878
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: IDA
    original_reference_id: PMID:15574878
    review:
      summary: 'Notch1 is expressed at the cell surface where it functions as a receptor for trans-acting ligands on neighboring cells.'
      action: ACCEPT
      reason: Cell surface localization is essential for Notch1 receptor function. The extracellular domain (N(EC)) binds ligands at the cell surface, triggering the proteolytic cascade.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0002437
      label: inflammatory response to antigenic stimulus
    evidence_type: IGI
    original_reference_id: PMID:17658279
    review:
      summary: 'Notch1 has evidence for involvement in inflammatory response to antigenic stimulus, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0006959
      label: humoral immune response
    evidence_type: IGI
    original_reference_id: PMID:17658279
    review:
      summary: 'Notch1 has evidence for involvement in humoral immune response, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003219
      label: cardiac right ventricle formation
    evidence_type: IMP
    original_reference_id: PMID:19620969
    review:
      summary: 'Notch1 has evidence for involvement in cardiac right ventricle formation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:19620969
    review:
      summary: 'Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex.'
      action: ACCEPT
      reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x).
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0090090
      label: negative regulation of canonical Wnt signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:19620969
    review:
      summary: 'Notch1 has evidence for involvement in negative regulation of canonical Wnt signaling pathway, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20547764
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030513
      label: positive regulation of BMP signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:20547764
    review:
      summary: 'Notch1 is involved in positive regulation of bmp signaling pathway.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:20547764
    review:
      summary: 'NICD positively regulates transcription by forming a coactivator complex with RBPJ and MAML that displaces corepressors.'
      action: ACCEPT
      reason: Notch1 NICD functions as a transcriptional activator. The NICD-RBPJ-MAML complex recruits coactivators like p300 to activate target gene transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:2000974
      label: negative regulation of pro-B cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:12032823
    review:
      summary: 'Notch1 is involved in negative regulation of pro-b cell differentiation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0046427
      label: positive regulation of receptor signaling pathway via JAK-STAT
    evidence_type: IDA
    original_reference_id: PMID:15156153
    review:
      summary: 'Notch1 is involved in positive regulation of receptor signaling pathway via jak-stat.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:12032823
    review:
      summary: 'Notch1 can negatively regulate certain genes through target gene specificity and crosstalk with repressive mechanisms.'
      action: KEEP_AS_NON_CORE
      reason: While Notch1 primarily activates transcription, it can also lead to repression of certain targets depending on context. This is a secondary regulatory outcome.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:12666205
    review:
      summary: 'NICD positively regulates transcription by forming a coactivator complex with RBPJ and MAML that displaces corepressors.'
      action: ACCEPT
      reason: Notch1 NICD functions as a transcriptional activator. The NICD-RBPJ-MAML complex recruits coactivators like p300 to activate target gene transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0048711
      label: positive regulation of astrocyte differentiation
    evidence_type: IDA
    original_reference_id: PMID:12666205
    review:
      summary: 'Notch1 positively regulates astrocyte differentiation via HES/HEY transcriptional targets.'
      action: KEEP_AS_NON_CORE
      reason: Positive regulation of astrocyte differentiation is a supported downstream neural-lineage output of Notch1 signaling, but it is not the general core receptor/NICD transcription function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0048715
      label: negative regulation of oligodendrocyte differentiation
    evidence_type: IDA
    original_reference_id: PMID:12666205
    review:
      summary: 'Notch1 negatively regulates oligodendrocyte differentiation, favoring astrocyte fate.'
      action: KEEP_AS_NON_CORE
      reason: Negative regulation of oligodendrocyte differentiation is a neural-lineage output of Notch1 signaling and should be retained as non-core rather than as the defining receptor/NICD function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060253
      label: negative regulation of glial cell proliferation
    evidence_type: IDA
    original_reference_id: PMID:12666205
    review:
      summary: 'Notch1 is involved in negative regulation of glial cell proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0072017
      label: distal tubule development
    evidence_type: IEP
    original_reference_id: PMID:15821257
    review:
      summary: 'Notch1 annotation to distal tubule development.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0072044
      label: collecting duct development
    evidence_type: IEP
    original_reference_id: PMID:15821257
    review:
      summary: 'Notch1 annotation to collecting duct development.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0072144
      label: glomerular mesangial cell development
    evidence_type: IEP
    original_reference_id: PMID:15821257
    review:
      summary: 'Notch1 annotation to glomerular mesangial cell development.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:19154718
    review:
      summary: 'Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex.'
      action: ACCEPT
      reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x).
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0009912
      label: auditory receptor cell fate commitment
    evidence_type: IMP
    original_reference_id: PMID:19154718
    review:
      summary: 'Notch1 has evidence for involvement in auditory receptor cell fate commitment, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045665
      label: negative regulation of neuron differentiation
    evidence_type: IGI
    original_reference_id: PMID:10205173
    review:
      summary: 'Notch1 is involved in negative regulation of neuron differentiation via Notch-mediated lateral inhibition, a canonical function in the neuron-glia binary fate decision.'
      action: KEEP_AS_NON_CORE
      reason: Notch1-mediated effects on neuron differentiation are well-supported developmental outputs, but they are tissue-context consequences of the core juxtacrine receptor/NICD transcription mechanism rather than the core function itself.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045955
      label: negative regulation of calcium ion-dependent exocytosis
    evidence_type: IMP
    original_reference_id: PMID:19251639
    review:
      summary: 'Notch1 has evidence for involvement in negative regulation of calcium ion-dependent exocytosis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0050679
      label: positive regulation of epithelial cell proliferation
    evidence_type: IGI
    original_reference_id: PMID:19251639
    review:
      summary: 'Notch1 has evidence for involvement in positive regulation of epithelial cell proliferation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0032495
      label: response to muramyl dipeptide
    evidence_type: IDA
    original_reference_id: PMID:21156799
    review:
      summary: 'Notch1 is involved in response to muramyl dipeptide.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030514
      label: negative regulation of BMP signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:19695258
    review:
      summary: 'Notch1 is involved in negative regulation of bmp signaling pathway.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045668
      label: negative regulation of osteoblast differentiation
    evidence_type: IMP
    original_reference_id: PMID:19695258
    review:
      summary: 'Notch1 is involved in negative regulation of osteoblast differentiation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0002051
      label: osteoblast fate commitment
    evidence_type: NAS
    original_reference_id: PMID:16025100
    review:
      summary: 'Notch1 has evidence for involvement in osteoblast fate commitment, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003160
      label: endocardium morphogenesis
    evidence_type: IEP
    original_reference_id: PMID:16025100
    review:
      summary: 'Notch1 regulates endocardium morphogenesis during heart development.'
      action: KEEP_AS_NON_CORE
      reason: Related to cardiac development - tissue-specific developmental function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:16025100
    review:
      summary: 'Notch1 is involved in negative regulation of dna-templated transcription.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060528
      label: secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development
    evidence_type: IMP
    original_reference_id: PMID:16360140
    review:
      summary: 'Notch1 has evidence for involvement in secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060740
      label: prostate gland epithelium morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:16360140
    review:
      summary: 'Notch1 has evidence for involvement in prostate gland epithelium morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0060768
      label: regulation of epithelial cell proliferation involved in prostate gland development
    evidence_type: IMP
    original_reference_id: PMID:16360140
    review:
      summary: 'Notch1 has evidence for involvement in regulation of epithelial cell proliferation involved in prostate gland development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0001701
      label: in utero embryonic development
    evidence_type: IMP
    original_reference_id: PMID:7789282
    review:
      summary: 'Notch1 has evidence for involvement in in utero embryonic development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007368
      label: determination of left/right symmetry
    evidence_type: IMP
    original_reference_id: PMID:7789282
    review:
      summary: 'Notch1 annotation to determination of left/right symmetry.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0014807
      label: regulation of somitogenesis
    evidence_type: IMP
    original_reference_id: PMID:7789282
    review:
      summary: 'Notch1 has evidence for involvement in regulation of somitogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0021915
      label: neural tube development
    evidence_type: IMP
    original_reference_id: PMID:7789282
    review:
      summary: 'Notch1 has evidence for involvement in neural tube development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0043069
      label: negative regulation of programmed cell death
    evidence_type: IMP
    original_reference_id: PMID:7789282
    review:
      summary: 'Notch1 has evidence for involvement in negative regulation of programmed cell death, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:16324690
    review:
      summary: 'The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription.'
      action: ACCEPT
      reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:9111338
    review:
      summary: 'NICD positively regulates transcription by forming a coactivator complex with RBPJ and MAML that displaces corepressors.'
      action: ACCEPT
      reason: Notch1 NICD functions as a transcriptional activator. The NICD-RBPJ-MAML complex recruits coactivators like p300 to activate target gene transcription.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10958687
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9315665
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0001889
      label: liver development
    evidence_type: IMP
    original_reference_id: PMID:15226394
    review:
      summary: 'Notch1 has evidence for involvement in liver development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010468
      label: regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:9102301
    review:
      summary: 'Notch1 has evidence for involvement in regulation of gene expression, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030182
      label: neuron differentiation
    evidence_type: IMP
    original_reference_id: PMID:9102301
    review:
      summary: 'Notch1 has evidence for involvement in neuron differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0050767
      label: regulation of neurogenesis
    evidence_type: IMP
    original_reference_id: PMID:9102301
    review:
      summary: 'Notch1 has evidence for involvement in regulation of neurogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2053963
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2066712
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2067638
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2071906
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2077477
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-2077479
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-2065902
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:17079689
    review:
      summary: 'The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription.'
      action: ACCEPT
      reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:17079689
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045618
      label: positive regulation of keratinocyte differentiation
    evidence_type: IGI
    original_reference_id: PMID:16618808
    review:
      summary: 'Notch1 has evidence for involvement in positive regulation of keratinocyte differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045618
      label: positive regulation of keratinocyte differentiation
    evidence_type: IDA
    original_reference_id: PMID:17079689
    review:
      summary: 'Notch1 has evidence for involvement in positive regulation of keratinocyte differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:16618808
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IGI
    original_reference_id: PMID:16618808
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0031490
      label: chromatin DNA binding
    evidence_type: IDA
    original_reference_id: PMID:17658278
    review:
      summary: 'Notch1 annotation to chromatin DNA binding.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:17658278
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0046533
      label: negative regulation of photoreceptor cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:16452096
    review:
      summary: 'Notch1 has evidence for involvement in negative regulation of photoreceptor cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:15965470
    review:
      summary: 'Cytoplasm'
      action: ACCEPT
      reason: NICD transits through cytoplasm.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0010001
      label: glial cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:15965470
    review:
      summary: 'Notch1 has evidence for involvement in glial cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:16607638
    review:
      summary: 'The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription.'
      action: ACCEPT
      reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007440
      label: foregut morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:16107537
    review:
      summary: 'Notch1 has evidence for involvement in foregut morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045165
      label: cell fate commitment
    evidence_type: IMP
    original_reference_id: PMID:16107537
    review:
      summary: 'cell fate commitment is consistent with canonical mouse Notch1 receptor biology.'
      action: ACCEPT
      reason: Falcon synthesis identifies the conserved Notch1 mechanism as ER/Golgi maturation, plasma-membrane ligand reception, regulated proteolysis, NICD nuclear entry, and CSL/RBPJ-MAML transcriptional activation.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0050678
      label: regulation of epithelial cell proliferation
    evidence_type: IMP
    original_reference_id: PMID:16107537
    review:
      summary: 'Notch1 has evidence for involvement in regulation of epithelial cell proliferation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0002040
      label: sprouting angiogenesis
    evidence_type: IMP
    original_reference_id: PMID:15809373
    review:
      summary: 'Notch1 has evidence for involvement in sprouting angiogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0031069
      label: hair follicle morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:15978571
    review:
      summary: 'Notch1 has evidence for involvement in hair follicle morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030326
      label: embryonic limb morphogenesis
    evidence_type: IGI
    original_reference_id: PMID:16169548
    review:
      summary: 'Notch1 has evidence for involvement in embryonic limb morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    evidence_type: IGI
    original_reference_id: PMID:16169548
    review:
      summary: 'Notch1 has evidence for involvement in positive regulation of apoptotic process, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0035116
      label: embryonic hindlimb morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:16245338
    review:
      summary: 'Notch1 has evidence for involvement in embryonic hindlimb morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:16145673
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0048754
      label: branching morphogenesis of an epithelial tube
    evidence_type: IMP
    original_reference_id: PMID:15064243
    review:
      summary: 'Notch1 has evidence for involvement in branching morphogenesis of an epithelial tube, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:10206645
    review:
      summary: 'The Notch1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription.'
      action: ACCEPT
      reason: Nuclear localization of NICD is essential for Notch1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007409
      label: axonogenesis
    evidence_type: IMP
    original_reference_id: PMID:16120638
    review:
      summary: 'Notch1 has evidence for involvement in axonogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030900
      label: forebrain development
    evidence_type: IMP
    original_reference_id: PMID:16120638
    review:
      summary: 'Notch1 has evidence for involvement in forebrain development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030900
      label: forebrain development
    evidence_type: IGI
    original_reference_id: PMID:16120638
    review:
      summary: 'Notch1 has evidence for involvement in forebrain development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045665
      label: negative regulation of neuron differentiation
    evidence_type: IMP
    original_reference_id: PMID:16120638
    review:
      summary: 'Notch1 is involved in negative regulation of neuron differentiation via Notch-mediated lateral inhibition, a canonical function in the neuron-glia binary fate decision.'
      action: KEEP_AS_NON_CORE
      reason: Notch1-mediated effects on neuron differentiation are well-supported developmental outputs, but they are tissue-context consequences of the core juxtacrine receptor/NICD transcription mechanism rather than the core function itself.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0048663
      label: neuron fate commitment
    evidence_type: IGI
    original_reference_id: PMID:16120638
    review:
      summary: 'Notch1 has evidence for involvement in neuron fate commitment, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:15902259
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0001708
      label: cell fate specification
    evidence_type: IMP
    original_reference_id: PMID:15068794
    review:
      summary: 'Notch1 has evidence for involvement in cell fate specification, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007409
      label: axonogenesis
    evidence_type: IDA
    original_reference_id: PMID:15598981
    review:
      summary: 'Notch1 has evidence for involvement in axonogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030154
      label: cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:12186854
    review:
      summary: 'Notch1 is a master regulator of cell-fate determination and differentiation across multiple tissue contexts.'
      action: ACCEPT
      reason: Cell differentiation regulation is a core biological role of Notch1 signaling. UniProt states Notch1 affects implementation of differentiation, proliferation and apoptotic programs.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030216
      label: keratinocyte differentiation
    evidence_type: IMP
    original_reference_id: PMID:15068794
    review:
      summary: 'Notch1 has evidence for involvement in keratinocyte differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0003682
      label: chromatin binding
    evidence_type: IDA
    original_reference_id: PMID:15689374
    review:
      summary: 'NICD associates with chromatin as part of the transcription activation complex with RBPJ.'
      action: ACCEPT
      reason: NICD binds to chromatin at target gene promoters as part of the RBPJ-MAML transcription complex. This is part of the core transcriptional mechanism.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IGI
    original_reference_id: PMID:15689374
    review:
      summary: 'Notch1 annotation to regulation of transcription by RNA polymerase II.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030324
      label: lung development
    evidence_type: IMP
    original_reference_id: PMID:15064243
    review:
      summary: 'Notch1 has evidence for involvement in lung development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045596
      label: negative regulation of cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:15064243
    review:
      summary: 'Notch1 has evidence for involvement in negative regulation of cell differentiation, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: IGI
    original_reference_id: PMID:15509736
    review:
      summary: 'Notch1 is involved in positive regulation of cell population proliferation.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:12783854
    review:
      summary: 'Notch1 is involved in positive regulation of transcription by rna polymerase ii.'
      action: KEEP_AS_NON_CORE
      reason: Context-dependent regulatory function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0048103
      label: somatic stem cell division
    evidence_type: IGI
    original_reference_id: PMID:15509736
    review:
      summary: 'Notch1 has evidence for involvement in somatic stem cell division, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0008544
      label: epidermis development
    evidence_type: IGI
    original_reference_id: PMID:15525534
    review:
      summary: 'Notch1 has evidence for involvement in epidermis development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0031069
      label: hair follicle morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:15525534
    review:
      summary: 'Notch1 has evidence for involvement in hair follicle morphogenesis, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    evidence_type: IDA
    original_reference_id: PMID:15081359
    review:
      summary: 'Notch1 has evidence for involvement in positive regulation of apoptotic process, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
    evidence_type: IMP
    original_reference_id: PMID:14701881
    review:
      summary: 'Notch1 promotes epithelial to mesenchymal transition.'
      action: KEEP_AS_NON_CORE
      reason: EMT regulation - context-dependent function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007492
      label: endoderm development
    evidence_type: IMP
    original_reference_id: PMID:14657333
    review:
      summary: 'Notch1 has evidence for involvement in endoderm development, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0030154
      label: cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:14657333
    review:
      summary: 'Notch1 is a master regulator of cell-fate determination and differentiation across multiple tissue contexts.'
      action: ACCEPT
      reason: Cell differentiation regulation is a core biological role of Notch1 signaling. UniProt states Notch1 affects implementation of differentiation, proliferation and apoptotic programs.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IC
    original_reference_id: PMID:10551863
    review:
      summary: 'Notch1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.'
      action: ACCEPT
      reason: Plasma membrane localization is essential for Notch1 receptor function. The mature Notch1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IC
    original_reference_id: PMID:10551863
    review:
      summary: 'Notch1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), Notch1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex.'
      action: ACCEPT
      reason: This is the core function of Notch1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x).
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0048103
      label: somatic stem cell division
    evidence_type: IDA
    original_reference_id: PMID:12717450
    review:
      summary: 'Notch1 has evidence for involvement in somatic stem cell division, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007368
      label: determination of left/right symmetry
    evidence_type: IMP
    original_reference_id: PMID:12730124
    review:
      summary: 'Notch1 annotation to determination of left/right symmetry.'
      action: KEEP_AS_NON_CORE
      reason: Transferred annotation - context-specific function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10551863
    review:
      summary: 'The protein binding annotation records a physical interaction but is too generic to describe Notch1 function.'
      action: REMOVE
      reason: Per curation guidance, generic protein binding should not be retained when the functional biology is a specific Notch receptor/ligand/coactivator pathway. Notch1 interactions are better captured by receptor activity, Notch signaling, and NICD-CSL/RBPJ-MAML transcriptional complex terms.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
  - term:
      id: GO:0007386
      label: compartment pattern specification
    evidence_type: IMP
    original_reference_id: PMID:12001066
    review:
      summary: 'Notch1 has evidence for involvement in compartment pattern specification, but this represents a tissue- or context-specific developmental/signaling output rather than the core receptor mechanism.'
      action: KEEP_AS_NON_CORE
      reason: The core Notch1 function is juxtacrine receptor signaling followed by NICD-mediated transcriptional regulation. This annotation is biologically plausible in mouse but is retained as non-core to avoid conflating downstream pleiotropic phenotypes with the primary molecular/cellular function.
      supported_by:
        - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
          supporting_text: '[Falcon deep-research synthesis used for this annotation decision.]'
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
    findings: []
  - id: GO_REF:0000096
    title: Automated transfer of experimentally-verified manual GO annotation data to mouse-rat orthologs
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning models
    findings: []
  - id: GO_REF:0000119
    title: Automated transfer of experimentally-verified manual GO annotation data to mouse-human orthologs
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10205173
    title: Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation.
    findings: []
  - id: PMID:10206645
    title: A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.
    findings: []
  - id: PMID:10551863
    title: Mouse jagged1 physically interacts with notch2 and other notch receptors. Assessment by quantitative methods.
    findings: []
  - id: PMID:10958687
    title: Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2.
    findings: []
  - id: PMID:11076679
    title: Oscillating expression of c-Hey2 in the presomitic mesoderm suggests that the segmentation clock may use combinatorial signaling through multiple interacting bHLH factors.
    findings: []
  - id: PMID:12001066
    title: Segmentation defects of Notch pathway mutants and absence of a synergistic phenotype in lunatic fringe/radical fringe double mutant mice.
    findings: []
  - id: PMID:12032823
    title: Overexpression of the Notch target genes Hes in vivo induces lymphoid and myeloid alterations.
    findings: []
  - id: PMID:12050162
    title: The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway.
    findings: []
  - id: PMID:12186854
    title: Notch1 control of oligodendrocyte differentiation in the spinal cord.
    findings: []
  - id: PMID:12666205
    title: Hes1 but not Hes5 regulates an astrocyte versus oligodendrocyte fate choice in glial restricted precursors.
    findings: []
  - id: PMID:12717450
    title: A role for Wnt signalling in self-renewal of haematopoietic stem cells.
    findings: []
  - id: PMID:12730124
    title: Notch signaling regulates left-right asymmetry determination by inducing Nodal expression.
    findings: []
  - id: PMID:12783854
    title: Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock.
    findings: []
  - id: PMID:12794108
    title: 'Notch-regulated ankyrin-repeat protein inhibits Notch1 signaling: multiple Notch1 signaling pathways involved in T cell development.'
    findings: []
  - id: PMID:14657333
    title: Notch signaling controls multiple steps of pancreatic differentiation.
    findings: []
  - id: PMID:14701881
    title: Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation.
    findings: []
  - id: PMID:15064243
    title: Functional diversity of notch family genes in fetal lung development.
    findings: []
  - id: PMID:15068794
    title: High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism.
    findings: []
  - id: PMID:15081359
    title: Notch activation induces apoptosis in neural progenitor cells through a p53-dependent pathway.
    findings: []
  - id: PMID:15107403
    title: The Notch target genes Hey1 and Hey2 are required for embryonic vascular development.
    findings: []
  - id: PMID:15156153
    title: Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling.
    findings: []
  - id: PMID:15226394
    title: Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors.
    findings: []
  - id: PMID:15509736
    title: Fibroblast growth factor receptor signaling promotes radial glial identity and interacts with Notch1 signaling in telencephalic progenitors.
    findings: []
  - id: PMID:15525534
    title: gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis.
    findings: []
  - id: PMID:15574878
    title: Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1.
    findings: []
  - id: PMID:15598981
    title: Targeted deletion of numb and numblike in sensory neurons reveals their essential functions in axon arborization.
    findings: []
  - id: PMID:15689374
    title: RBPjkappa-dependent Notch function regulates Gata2 and is essential for the formation of intra-embryonic hematopoietic cells.
    findings: []
  - id: PMID:15809373
    title: Essential role of endothelial Notch1 in angiogenesis.
    findings: []
  - id: PMID:15821257
    title: Segmental expression of Notch and Hairy genes in nephrogenesis.
    findings: []
  - id: PMID:15902259
    title: The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity.
    findings: []
  - id: PMID:15965470
    title: DNER acts as a neuron-specific Notch ligand during Bergmann glial development.
    findings: []
  - id: PMID:15978571
    title: Notch1 is essential for postnatal hair follicle development and homeostasis.
    findings: []
  - id: PMID:16025100
    title: Mutations in NOTCH1 cause aortic valve disease.
    findings: []
  - id: PMID:16107537
    title: Direct regulation of intestinal fate by Notch.
    findings: []
  - id: PMID:16120638
    title: Notch signaling coordinates the patterning of striatal compartments.
    findings: []
  - id: PMID:16145673
    title: 'Fjx1: a notch-inducible secreted ligand with specific binding sites in developing mouse embryos and adult brain.'
    findings: []
  - id: PMID:16169548
    title: Notch1 and 2 cooperate in limb ectoderm to receive an early Jagged2 signal regulating interdigital apoptosis.
    findings: []
  - id: PMID:16245338
    title: Notch1 signals through Jagged2 to regulate apoptosis in the apical ectodermal ridge of the developing limb bud.
    findings: []
  - id: PMID:16324690
    title: BMP7 inhibits branching morphogenesis in the prostate gland and interferes with Notch signaling.
    findings: []
  - id: PMID:16360140
    title: Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation.
    findings: []
  - id: PMID:16452096
    title: Notch 1 inhibits photoreceptor production in the developing mammalian retina.
    findings: []
  - id: PMID:16607638
    title: Jag2-Notch1 signaling regulates oral epithelial differentiation and palate development.
    findings: []
  - id: PMID:16618808
    title: Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation.
    findings: []
  - id: PMID:17079689
    title: Canonical notch signaling functions as a commitment switch in the epidermal lineage.
    findings: []
  - id: PMID:17210915
    title: Baf60c is a nuclear Notch signaling component required for the establishment of left-right asymmetry.
    findings: []
  - id: PMID:17303760
    title: Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition.
    findings: []
  - id: PMID:17336907
    title: Notch signaling is essential for ventricular chamber development.
    findings: []
  - id: PMID:17573339
    title: Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor.
    findings: []
  - id: PMID:17658278
    title: Notch directly regulates Gata3 expression during T helper 2 cell differentiation.
    findings: []
  - id: PMID:17658279
    title: Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch.
    findings: []
  - id: PMID:17685488
    title: 'Monitoring Notch1 activity in development: evidence for a feedback regulatory loop.'
    findings: []
  - id: PMID:18299578
    title: Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways.
    findings: []
  - id: PMID:18430783
    title: Zfp64 participates in Notch signaling and regulates differentiation in mesenchymal cells.
    findings: []
  - id: PMID:18676613
    title: The intracellular region of Notch ligands Dll1 and Dll3 regulates their trafficking and signaling activity.
    findings: []
  - id: PMID:18952909
    title: Artery and vein size is balanced by Notch and ephrin B2/EphB4 during angiogenesis.
    findings: []
  - id: PMID:19154718
    title: Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti.
    findings: []
  - id: PMID:19245366
    title: MYPT1, the targeting subunit of smooth-muscle myosin phosphatase, is a substrate for the asparaginyl hydroxylase factor inhibiting hypoxia-inducible factor (FIH).
    findings: []
  - id: PMID:19251639
    title: Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine.
    findings: []
  - id: PMID:19620969
    title: A regulatory pathway involving Notch1/beta-catenin/Isl1 determines cardiac progenitor cell fate.
    findings: []
  - id: PMID:19695258
    title: Notch1 represses osteogenic pathways in aortic valve cells.
    findings: []
  - id: PMID:20007915
    title: Distinct roles for cell-autonomous Notch signaling in cardiomyocytes of the embryonic and adult heart.
    findings: []
  - id: PMID:20547764
    title: ZFP423 coordinates Notch and bone morphogenetic protein signaling, selectively up-regulating Hes5 gene expression.
    findings: []
  - id: PMID:20890042
    title: Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation.
    findings: []
  - id: PMID:21102556
    title: RITA, a novel modulator of Notch signalling, acts via nuclear export of RBP-J.
    findings: []
  - id: PMID:21156799
    title: Intracellular pathogen sensor NOD2 programs macrophages to trigger Notch1 activation.
    findings: []
  - id: PMID:21191019
    title: A protein (ORF2) encoded by the latency-related gene of bovine herpesvirus 1 interacts with Notch1 and Notch3.
    findings: []
  - id: PMID:21266778
    title: Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways.
    findings: []
  - id: PMID:21311046
    title: Differential Notch signaling in the epicardium is required for cardiac inflow development and coronary vessel morphogenesis.
    findings: []
  - id: PMID:21315255
    title: Activity-induced Notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks.
    findings: []
  - id: PMID:21419176
    title: The EGF-like proteins DLK1 and DLK2 function as inhibitory non-canonical ligands of NOTCH1 receptor that modulate each other's activities.
    findings: []
  - id: PMID:21493891
    title: Diet-induced aortic valve disease in mice haploinsufficient for the Notch pathway effector RBPJK/CSL.
    findings: []
  - id: PMID:21985982
    title: Delta-like 1-Lysine613 regulates notch signaling.
    findings: []
  - id: PMID:22110751
    title: Inhibitory role of Notch1 in calcific aortic valve disease.
    findings: []
  - id: PMID:22147266
    title: Analysis of early C2C12 myogenesis identifies stably and differentially expressed transcriptional regulators whose knock-down inhibits myoblast differentiation.
    findings: []
  - id: PMID:22258620
    title: Pten coordinates retinal neurogenesis by regulating Notch signalling.
    findings: []
  - id: PMID:23160044
    title: BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets.
    findings: []
  - id: PMID:23284756
    title: Ascl1 (Mash1) knockout perturbs differentiation of nonneuronal cells in olfactory epithelium.
    findings: []
  - id: PMID:23382219
    title: Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.
    findings: []
  - id: PMID:23583836
    title: Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease.
    findings: []
  - id: PMID:24667410
    title: Notch4 reveals a novel mechanism regulating Notch signal transduction.
    findings: []
  - id: PMID:24715457
    title: Cadherin-based adhesions in the apical endfoot are required for active Notch signaling to control neurogenesis in vertebrates.
    findings: []
  - id: PMID:25038826
    title: Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity.
    findings: []
  - id: PMID:25535395
    title: Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway.
    findings: []
  - id: PMID:26491108
    title: Notch-Tnf signalling is required for development and homeostasis of arterial valves.
    findings: []
  - id: PMID:26635527
    title: Notch1 Regulates Hippocampal Plasticity Through Interaction with the Reelin Pathway, Glutamatergic Transmission and CREB Signaling.
    findings: []
  - id: PMID:27107132
    title: Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract.
    findings: []
  - id: PMID:27719760
    title: BLOS2 negatively regulates Notch signaling during neural and hematopoietic stem and progenitor cell development.
    findings: []
  - id: PMID:28089369
    title: 'Deciphering the Fringe-Mediated Notch Code: Identification of Activating and Inhibiting Sites Allowing Discrimination between Ligands.'
    findings: []
  - id: PMID:28498977
    title: Consequences of MEGF10 deficiency on myoblast function and Notch1 interactions.
    findings: []
  - id: PMID:28561022
    title: IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression.
    findings: []
  - id: PMID:38891776
    title: Pin1 Downregulation Is Involved in Excess Retinoic Acid-Induced Failure of Neural Tube Closure.
    findings: []
  - id: PMID:7789282
    title: Notch1 is required for the coordinate segmentation of somites.
    findings: []
  - id: PMID:8749394
    title: Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H).
    findings: []
  - id: PMID:9102301
    title: Conservation of the Notch signalling pathway in mammalian neurogenesis.
    findings: []
  - id: PMID:9111338
    title: RBP-L, a transcription factor related to RBP-Jkappa.
    findings: []
  - id: PMID:9315665
    title: Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor.
    findings: []
  - id: Reactome:R-MMU-2023158
    title: Glycosylation of Pre-Notch by Fringe
    findings: []
  - id: Reactome:R-MMU-2023179
    title: Glucosylation of Pre-Notch by Poglut1
    findings: []
  - id: Reactome:R-MMU-2032750
    title: Sel1l negatively regulates Pre-Notch exit from endoplasmic reticulum
    findings: []
  - id: Reactome:R-MMU-2053938
    title: Dll4 binds Notch1
    findings: []
  - id: Reactome:R-MMU-2053963
    title: Notch1 binds Jag1
    findings: []
  - id: Reactome:R-MMU-2066712
    title: Dner binds Notch1
    findings: []
  - id: Reactome:R-MMU-2067638
    title: Gamma secretase cleaves Dner:Notch1 complex
    findings: []
  - id: Reactome:R-MMU-2071906
    title: Notch1 binds Dlk1
    findings: []
  - id: Reactome:R-MMU-2077477
    title: Numb recruits Itch to Notch1
    findings: []
  - id: Reactome:R-MMU-2077479
    title: Itch ubiquitinates Notch
    findings: []
  - id: Reactome:R-MMU-209285
    title: The transmembrane complex Murine gamma-secretase cleaves Murine NEXT at the S3 site leaving NTM and releasing NICD into the cytoplasm
    findings: []
  - id: Reactome:R-MMU-4396387
    title: mNOTCH1 coactivator complex bind promoters of Hey genes
    findings: []
  - id: Reactome:R-MMU-9667655
    title: Nbea binds nicd1
    findings: []
  - id: Reactome:R-MMU-9793875
    title: Dll3 binds Notch1
    findings: []
  - id: Reactome:R-MMU-9824206
    title: Lef1:Ctnnb1, Nicd (Notch), and Tbx6 bind the Hes7 gene in presomitic mesoderm
    findings: []
  - id: Reactome:R-MMU-9824230
    title: Hes7 binds the Lfng gene
    findings: []
  - id: Reactome:R-MMU-9824231
    title: Rbpj:Nicd and Msgn1 bind the Lfng gene
    findings: []
  - id: Reactome:R-MMU-9824249
    title: Expression of Notch1 in presomitic mesoderm
    findings: []
  - id: Reactome:R-MMU-9824278
    title: Hes7 binds the Hes7 gene
    findings: []
  - id: Reactome:R-NUL-1986584
    title: Fucosylation of Pre-Notch by POFUT1
    findings: []
  - id: Reactome:R-NUL-2063915
    title: ADAM17 cleaves Notch1 at S2
    findings: []
  - id: Reactome:R-NUL-2064853
    title: FBXW7 binds phosphorylated NICD1
    findings: []
  - id: Reactome:R-NUL-2064883
    title: FBXW7 mediates ubiquitination of phosphorylated NICD1
    findings: []
  - id: Reactome:R-NUL-2065560
    title: mNICD1 binds HIF1A
    findings: []
  - id: Reactome:R-NUL-2065902
    title: Gamma secretase complex cleaves Cntn1-actived Notch1
    findings: []
  - id: Reactome:R-NUL-209162
    title: Murine ADAM10 cleaves Notch at the S2 site producing transmembrane spanning NEXT and ligand-bound NECD
    findings: []
  - id: Reactome:R-NUL-4396363
    title: mNICD1 Chimeric Enhancer Complex binds Hes1 promoter
    findings: []
  - id: file:mouse/Notch1/Notch1-deep-research-falcon.md
    title: Falcon deep research report on mouse Notch1 function
    findings: []
  - id: file:interpro/panther/PTHR45836/PTHR45836-metadata.yaml
    title: PANTHER PTHR45836 Notch and Slit guidance protein family metadata
    findings: []
  - id: file:interpro/panther/PTHR45836/PTHR45836-entries.csv
    title: Reviewed protein members for PANTHER PTHR45836
    findings: []
core_functions:
  - description: Notch1 functions as a transmembrane signaling receptor at the plasma membrane, responding to membrane-bound DLL/Jagged-family ligands on neighboring cells and transducing cell-cell contact signals through regulated intramembrane proteolysis.
    molecular_function:
      id: GO:0004888
      label: transmembrane signaling receptor activity
    directly_involved_in:
      - id: GO:0007219
        label: Notch signaling pathway
      - id: GO:0030154
        label: cell differentiation
    locations:
      - id: GO:0005886
        label: plasma membrane
      - id: GO:0009986
        label: cell surface
    supported_by:
      - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
        supporting_text: '[Falcon synthesis describes Notch1 as a mechanosensitive juxtacrine receptor activated by ligand-dependent cleavage.]'
  - description: The cleaved Notch1 intracellular domain (NICD) functions as a transcriptional coactivator in the nucleus by binding CSL/RBPJ and recruiting MAML to activate canonical Notch target genes such as Hes and Hey family members.
    molecular_function:
      id: GO:0003713
      label: transcription coactivator activity
    directly_involved_in:
      - id: GO:0045893
        label: positive regulation of DNA-templated transcription
      - id: GO:0007221
        label: positive regulation of transcription of Notch receptor target
    locations:
      - id: GO:0005634
        label: nucleus
    in_complex:
      id: GO:0002193
      label: MAML1-RBP-Jkappa- ICN1 complex
    supported_by:
      - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
        supporting_text: '[Falcon synthesis describes NICD nuclear entry and CSL/RBPJ-MAML target gene activation.]'
  - description: Notch1 EGF-like repeats bind calcium ions, which supports receptor folding, stability, and ligand-binding competence.
    molecular_function:
      id: GO:0005509
      label: calcium ion binding
    locations:
      - id: GO:0005886
        label: plasma membrane
    supported_by:
      - reference_id: file:mouse/Notch1/Notch1-deep-research-falcon.md
        supporting_text: '[Falcon synthesis identifies Notch1 as an EGF-repeat transmembrane receptor with ligand-binding extracellular modules.]'

Notch1

Gene Description

Existing Annotations Review

Core Functions

Notch1 functions as a transmembrane signaling receptor at the plasma membrane, responding to membrane-bound DLL/Jagged-family ligands on neighboring cells and transducing cell-cell contact signals through regulated intramembrane proteolysis.

The cleaved Notch1 intracellular domain (NICD) functions as a transcriptional coactivator in the nucleus by binding CSL/RBPJ and recruiting MAML to activate canonical Notch target genes such as Hes and Hey family members.

Notch1 EGF-like repeats bind calcium ions, which supports receptor folding, stability, and ligand-binding competence.

References

📚 Additional Documentation

Deep Research Bioreason

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Bioreason Rl

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Research Report: Functional Annotation of Mouse Notch1 (UniProt Q01705)

0) Target verification (mandatory)

1) Key concepts and definitions (current understanding)

1.1 Notch signaling is juxtacrine and force dependent

1.2 Protein architecture (functional modules)

1.3 Canonical activation mechanism and key cleavage steps (S1/S2/S3)

1.4 Nuclear transcriptional complex and canonical targets

1.5 Subcellular localization summary

2) Recent developments and latest research (prioritizing 2023–2024)

2.1 Vascular homeostasis: Dll4 loss does not phenocopy Notch1/Rbpj loss (adult endothelium)

2.2 Brain endothelium/BBB integrity: DLL4–NOTCH1–CLDN5 axis and hyperoxia vulnerability

2.3 CNS neuroinflammation: astrocytic DLL4–NOTCH1 drives IL-6/STAT3 reactivity and BBB dysfunction

2.4 Metabolism/cancer cachexia: endothelial Notch1 in adipose tissue as a long-range wasting driver

2.5 Immune function in vivo: Notch receptor signaling in CD4+ T cells during tissue repair

3) Functional annotation: primary molecular function, pathways, localization

3.1 Primary molecular function (signaling role)

3.2 Pathway placement and core steps (mouse Notch1)

3.3 Protein turnover and signal termination

4) Current applications and real-world implementations

4.1 Therapeutic modulation strategies (expert review synthesis)

4.2 Receptor-selective targeting: anti-Notch1 antibody in melanoma models (2024)

4.3 Targeting downstream effector pathways: RA blockade in cachexia (2023)

5) Relevant statistics and quantitative data (from recent studies)

6) Expert interpretation and synthesis (authoritative perspective)

6.1 Why Notch1 is “context-dependent” yet mechanistically precise

6.2 A 2023–2024 refinement: ligand vs receptor perturbations are not interchangeable in adult vessels

7) Summary evidence map (for functional annotation)

8) Retrieved visual evidence (schematic)

References (URLs and publication dates)

Citations

Deep Research Openai

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Notch1 (Mus musculus) – Function and Biological Roles

Introduction and Key Concepts

Activation Mechanism and Signaling Pathway