Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006874 intracellular calcium ion homeostasis	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: intracellular calcium ion homeostasis is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Kidney and podocyte disease evidence: Endothelin-1 stimulation of primary mouse podocytes "elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)" and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.
GO:0045987 positive regulation of smooth muscle contraction	IBA GO_REF:0000033	ACCEPT	Summary: positive regulation of smooth muscle contraction is biologically consistent with the curated synthesis for Edn1 and is supported by IBA evidence (GO_REF:0000033). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure." file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon identifies ET-1 as a potent vasoconstrictor whose ETA signaling in vascular smooth muscle promotes sustained contraction.
GO:0003100 regulation of systemic arterial blood pressure by endothelin	IBA GO_REF:0000033	ACCEPT	Summary: regulation of systemic arterial blood pressure by endothelin is biologically consistent with the curated synthesis for Edn1 and is supported by IBA evidence (GO_REF:0000033). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure." file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon summarizes ET-1 as a central regulator of vascular tone and blood pressure through receptor-specific endothelin signaling.
GO:0005179 hormone activity	IBA GO_REF:0000033	ACCEPT	Summary: hormone activity is biologically consistent with the curated synthesis for Edn1 and is supported by IBA evidence (GO_REF:0000033). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon describes Edn1 as encoding a secreted peptide hormone precursor that yields mature endothelin-1, supporting hormone/receptor ligand activity.
GO:0005615 extracellular space	IBA GO_REF:0000033	ACCEPT	Summary: extracellular space is biologically consistent with the curated synthesis for Edn1 and is supported by IBA evidence (GO_REF:0000033). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon states that ET-1 functions as an extracellular ligand produced by endothelial and epithelial cells.
GO:0014826 vein smooth muscle contraction	IBA GO_REF:0000033	ACCEPT	Summary: vein smooth muscle contraction is biologically consistent with the curated synthesis for Edn1 and is supported by IBA evidence (GO_REF:0000033). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0031707 endothelin A receptor binding	IBA GO_REF:0000033	ACCEPT	Summary: endothelin A receptor binding is biologically consistent with the curated synthesis for Edn1 and is supported by IBA evidence (GO_REF:0000033). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon reports that mature ET-1 signals through ETA/EDNRA receptors, supporting endothelin A receptor binding.
GO:0031708 endothelin B receptor binding	IBA GO_REF:0000033	ACCEPT	Summary: endothelin B receptor binding is biologically consistent with the curated synthesis for Edn1 and is supported by IBA evidence (GO_REF:0000033). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon reports that mature ET-1 signals through ETB/EDNRB receptors, supporting endothelin B receptor binding.
GO:0005576 extracellular region	IEA GO_REF:0000120	ACCEPT	Summary: extracellular region is biologically consistent with the curated synthesis for Edn1 and is supported by IEA evidence (GO_REF:0000120). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon states that ET-1 functions as an extracellular ligand produced by endothelial and epithelial cells.
GO:0019229 regulation of vasoconstriction	IEA GO_REF:0000002	MODIFY	Summary: regulation of vasoconstriction captures the right general biology for Edn1, but a more specific GO term is available. Reason: The current term is too broad or less precise than vasoconstriction for this gene. Replace with vasoconstriction to align the annotation with the reviewed evidence. Proposed replacements: vasoconstriction Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0042310 vasoconstriction	IEA GO_REF:0000120	ACCEPT	Summary: vasoconstriction is biologically consistent with the curated synthesis for Edn1 and is supported by IEA evidence (GO_REF:0000120). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0097746 blood vessel diameter maintenance	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: blood vessel diameter maintenance is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0000122 negative regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: negative regulation of transcription by RNA polymerase II is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0001666 response to hypoxia	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: response to hypoxia is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0001821 histamine secretion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: histamine secretion is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0003100 regulation of systemic arterial blood pressure by endothelin	IEA GO_REF:0000107	ACCEPT	Summary: regulation of systemic arterial blood pressure by endothelin is biologically consistent with the curated synthesis for Edn1 and is supported by IEA evidence (GO_REF:0000107). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure." file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon summarizes ET-1 as a central regulator of vascular tone and blood pressure through receptor-specific endothelin signaling.
GO:0005125 cytokine activity	IEA GO_REF:0000107	MODIFY	Summary: cytokine activity captures the right general biology for Edn1, but a more specific GO term is available. Reason: The current term is too broad or less precise than receptor ligand activity for this gene. Replace with receptor ligand activity to align the annotation with the reviewed evidence. Proposed replacements: receptor ligand activity Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB.
GO:0005179 hormone activity	IEA GO_REF:0000107	ACCEPT	Summary: hormone activity is biologically consistent with the curated synthesis for Edn1 and is supported by IEA evidence (GO_REF:0000107). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon describes Edn1 as encoding a secreted peptide hormone precursor that yields mature endothelin-1, supporting hormone/receptor ligand activity.
GO:0005615 extracellular space	IEA GO_REF:0000120	ACCEPT	Summary: extracellular space is biologically consistent with the curated synthesis for Edn1 and is supported by IEA evidence (GO_REF:0000120). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon states that ET-1 functions as an extracellular ligand produced by endothelial and epithelial cells.
GO:0005737 cytoplasm	IEA GO_REF:0000107	REMOVE	Summary: cytoplasm is not supported as an appropriate annotation for Edn1 after review of the available mouse evidence. Reason: The term appears to reflect either an unsupported transfer, a paralog/family overreach, or a localization/process inconsistent with the curated Edn1 biology. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0006874 intracellular calcium ion homeostasis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: intracellular calcium ion homeostasis is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Kidney and podocyte disease evidence: Endothelin-1 stimulation of primary mouse podocytes "elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)" and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.
GO:0007166 cell surface receptor signaling pathway	IEA GO_REF:0000107	MODIFY	Summary: cell surface receptor signaling pathway captures the right general biology for Edn1, but a more specific GO term is available. Reason: The current term is too broad or less precise than endothelin receptor signaling pathway for this gene. Replace with endothelin receptor signaling pathway to align the annotation with the reviewed evidence. Proposed replacements: endothelin receptor signaling pathway Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0007186 G protein-coupled receptor signaling pathway	IEA GO_REF:0000107	MODIFY	Summary: G protein-coupled receptor signaling pathway captures the right general biology for Edn1, but a more specific GO term is available. Reason: The current term is too broad or less precise than endothelin receptor signaling pathway for this gene. Replace with endothelin receptor signaling pathway to align the annotation with the reviewed evidence. Proposed replacements: endothelin receptor signaling pathway Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0007204 positive regulation of cytosolic calcium ion concentration	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of cytosolic calcium ion concentration is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0007267 cell-cell signaling	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: cell-cell signaling is biologically consistent with secreted paracrine Edn1 ligand activity but is less specific than endothelin receptor signaling. Reason: Edn1 is a secreted peptide ligand that mediates receptor-dependent communication between cells; retain the broad signaling term as non-core while preferring endothelin receptor signaling and receptor ligand terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB.
GO:0008217 regulation of blood pressure	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: regulation of blood pressure is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0008284 positive regulation of cell population proliferation	IEA GO_REF:0000120	MARK AS OVER ANNOTATED	Summary: positive regulation of cell population proliferation is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0009410 response to xenobiotic stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: response to xenobiotic stimulus is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0010193 response to ozone	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: response to ozone is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0010460 positive regulation of heart rate	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of heart rate is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: PMID:23933587 Edn1 and Ednra knock-out mice demonstrate abnormalities in pharyngeal arch artery patterning
GO:0010613 positive regulation of cardiac muscle hypertrophy	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of cardiac muscle hypertrophy is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0010629 negative regulation of gene expression	IEA GO_REF:0000120	MARK AS OVER ANNOTATED	Summary: negative regulation of gene expression is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0014823 response to activity	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: response to activity is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0014824 artery smooth muscle contraction	IEA GO_REF:0000120	ACCEPT	Summary: artery smooth muscle contraction is a direct vascular output of endothelin-1 receptor signaling. Reason: ET-1 is a vasoactive peptide ligand whose ETA/EDNRA signaling in vascular smooth muscle drives vasoconstriction through PLC/calcium signaling, making this term consistent with the curated vascular contraction function. Supporting Evidence: file:mouse/Edn1/Edn1-deep-research-falcon.md ETA (EDNRA/ETAR): classically enriched on vascular smooth muscle cells (VSMCs) and mediates potent, sustained vasoconstriction and growth/remodeling programs.
GO:0014826 vein smooth muscle contraction	IEA GO_REF:0000107	ACCEPT	Summary: vein smooth muscle contraction is biologically consistent with the curated synthesis for Edn1 and is supported by IEA evidence (GO_REF:0000107). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0019722 calcium-mediated signaling	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: calcium-mediated signaling is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0023019 signal transduction involved in regulation of gene expression	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: signal transduction involved in regulation of gene expression is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0030072 peptide hormone secretion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: peptide hormone secretion is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0030185 nitric oxide transport	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: nitric oxide transport is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0030335 positive regulation of cell migration	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of cell migration is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0031707 endothelin A receptor binding	IEA GO_REF:0000120	ACCEPT	Summary: endothelin A receptor binding is biologically consistent with the curated synthesis for Edn1 and is supported by IEA evidence (GO_REF:0000120). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon reports that mature ET-1 signals through ETA/EDNRA receptors, supporting endothelin A receptor binding.
GO:0031708 endothelin B receptor binding	IEA GO_REF:0000120	ACCEPT	Summary: endothelin B receptor binding is biologically consistent with the curated synthesis for Edn1 and is supported by IEA evidence (GO_REF:0000120). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon reports that mature ET-1 signals through ETB/EDNRB receptors, supporting endothelin B receptor binding.
GO:0032308 positive regulation of prostaglandin secretion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of prostaglandin secretion is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0032496 response to lipopolysaccharide	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: response to lipopolysaccharide is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0033093 Weibel-Palade body	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Weibel-Palade body localization reflects endothelial regulated storage/secretion of ET-1 precursor-processing components. Reason: This supports regulated endothelial storage and secretion of ET-1, but remains a localization/trafficking context rather than the core ligand signaling role. Supporting Evidence: file:mouse/Edn1/Edn1-deep-research-falcon.md ET-1 precursors and processing components can be stored in endothelial secretory vesicles, particularly Weibel-Palade bodies, with reported co-localization of pro-ET-1 and ECE-1.
GO:0033574 response to testosterone	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: response to testosterone is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0034392 negative regulation of smooth muscle cell apoptotic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: negative regulation of smooth muscle cell apoptotic process is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0034696 response to prostaglandin F	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: response to prostaglandin F is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0035094 response to nicotine	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: response to nicotine is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0035556 intracellular signal transduction	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: intracellular signal transduction is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0035994 response to muscle stretch	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: response to muscle stretch is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0042045 epithelial fluid transport	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: epithelial fluid transport is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0042482 positive regulation of odontogenesis	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of odontogenesis is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0042554 superoxide anion generation	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: superoxide anion generation is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0043200 response to amino acid	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: response to amino acid is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0043410 positive regulation of MAPK cascade	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of MAPK cascade is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: phosphatidylinositol 3-kinase/protein kinase B signal transduction is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0044321 response to leptin	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: response to leptin is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0045178 basal part of cell	IEA GO_REF:0000107	UNDECIDED	Summary: The local evidence supports Edn1 as a secreted ligand but does not verify this specific basal-cell localization. Reason: The generic secreted-ligand evidence and Weibel-Palade storage model do not establish a basal part of cell annotation for Edn1.
GO:0045793 positive regulation of cell size	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of cell size is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0045840 positive regulation of mitotic nuclear division	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of mitotic nuclear division is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000120	MARK AS OVER ANNOTATED	Summary: positive regulation of transcription by RNA polymerase II is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0045987 positive regulation of smooth muscle contraction	IEA GO_REF:0000107	ACCEPT	Summary: positive regulation of smooth muscle contraction is biologically consistent with the curated synthesis for Edn1 and is supported by IEA evidence (GO_REF:0000107). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure." file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon identifies ET-1 as a potent vasoconstrictor whose ETA signaling in vascular smooth muscle promotes sustained contraction.
GO:0046330 positive regulation of JNK cascade	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of JNK cascade is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0046887 positive regulation of hormone secretion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of hormone secretion is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0046888 negative regulation of hormone secretion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: negative regulation of hormone secretion is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0048237 rough endoplasmic reticulum lumen	IEA GO_REF:0000107	UNDECIDED	Summary: The local evidence supports Edn1 as a secreted peptide precursor, but does not verify a rough endoplasmic reticulum lumen localization. Reason: Secretory-protein biology alone is not enough to retain this specific automated cellular-component annotation without direct localization evidence.
GO:0048661 positive regulation of smooth muscle cell proliferation	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of smooth muscle cell proliferation is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0050850 positive regulation of calcium-mediated signaling	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of calcium-mediated signaling is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0051248 negative regulation of protein metabolic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: negative regulation of protein metabolic process is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0051899 membrane depolarization	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: membrane depolarization is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0060137 maternal process involved in parturition	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: maternal process involved in parturition is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0060298 positive regulation of sarcomere organization	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of sarcomere organization is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0061051 positive regulation of cell growth involved in cardiac muscle cell development	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of cell growth involved in cardiac muscle cell development is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: PMID:23933587 Edn1/Ednra signaling is involved in pharyngeal artery development by controlling the fate of neural crest cells
GO:0070301 cellular response to hydrogen peroxide	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to hydrogen peroxide is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0071277 cellular response to calcium ion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to calcium ion is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0071346 cellular response to type II interferon	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to type II interferon is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0071347 cellular response to interleukin-1	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to interleukin-1 is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0071356 cellular response to tumor necrosis factor	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to tumor necrosis factor is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0071375 cellular response to peptide hormone stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to peptide hormone stimulus is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0071385 cellular response to glucocorticoid stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to glucocorticoid stimulus is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0071389 cellular response to mineralocorticoid stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to mineralocorticoid stimulus is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0071398 cellular response to fatty acid	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to fatty acid is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0071456 cellular response to hypoxia	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to hypoxia is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0071466 cellular response to xenobiotic stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to xenobiotic stimulus is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0071548 response to dexamethasone	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: response to dexamethasone is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0071559 response to transforming growth factor beta	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: response to transforming growth factor beta is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0071560 cellular response to transforming growth factor beta stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to transforming growth factor beta stimulus is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0086100 endothelin receptor signaling pathway	IEA GO_REF:0000107	ACCEPT	Summary: endothelin receptor signaling pathway is biologically consistent with the curated synthesis for Edn1 and is supported by IEA evidence (GO_REF:0000107). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core receptor binding and signaling: Endothelin stimulates high-affinity receptor binding and phospholipase C signaling in fibroblasts; the abstract reports that endothelin "specifically binds to a single class of high affinity receptors" and "stimulates phospholipase C with the production of second messengers inositol trisphosphate and 1,2-diacylglycerol." file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon summarizes the canonical endothelin receptor pathway: ET-1 activates ETA/ETB GPCRs with Gq/11-PLC-calcium/PKC and other downstream signaling.
GO:0090023 positive regulation of neutrophil chemotaxis	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of neutrophil chemotaxis is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0097237 cellular response to toxic substance	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to toxic substance is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0141156 cAMP/PKA signal transduction	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cAMP/PKA signal transduction is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0160195 negative regulation of phospholipase C/protein kinase C signal transduction	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: negative regulation of phospholipase C/protein kinase C signal transduction is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:1901224 positive regulation of non-canonical NF-kappaB signal transduction	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of non-canonical NF-kappaB signal transduction is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:1902074 response to salt	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: response to salt is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:1904707 positive regulation of vascular associated smooth muscle cell proliferation	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of vascular associated smooth muscle cell proliferation is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0000122 negative regulation of transcription by RNA polymerase II	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: negative regulation of transcription by RNA polymerase II is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0003100 regulation of systemic arterial blood pressure by endothelin	ISO GO_REF:0000119	ACCEPT	Summary: regulation of systemic arterial blood pressure by endothelin is biologically consistent with the curated synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000119). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure." file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon summarizes ET-1 as a central regulator of vascular tone and blood pressure through receptor-specific endothelin signaling.
GO:0005125 cytokine activity	ISO GO_REF:0000119	MODIFY	Summary: cytokine activity captures the right general biology for Edn1, but a more specific GO term is available. Reason: The current term is too broad or less precise than receptor ligand activity for this gene. Replace with receptor ligand activity to align the annotation with the reviewed evidence. Proposed replacements: receptor ligand activity Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB.
GO:0005179 hormone activity	ISO GO_REF:0000119	ACCEPT	Summary: hormone activity is biologically consistent with the curated synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000119). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon describes Edn1 as encoding a secreted peptide hormone precursor that yields mature endothelin-1, supporting hormone/receptor ligand activity.
GO:0005615 extracellular space	ISO GO_REF:0000119	ACCEPT	Summary: extracellular space is biologically consistent with the curated synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000119). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon states that ET-1 functions as an extracellular ligand produced by endothelial and epithelial cells.
GO:0005737 cytoplasm	ISO GO_REF:0000119	REMOVE	Summary: cytoplasm is not supported as an appropriate annotation for Edn1 after review of the available mouse evidence. Reason: The term appears to reflect either an unsupported transfer, a paralog/family overreach, or a localization/process inconsistent with the curated Edn1 biology. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0007166 cell surface receptor signaling pathway	ISO GO_REF:0000119	MODIFY	Summary: cell surface receptor signaling pathway captures the right general biology for Edn1, but a more specific GO term is available. Reason: The current term is too broad or less precise than endothelin receptor signaling pathway for this gene. Replace with endothelin receptor signaling pathway to align the annotation with the reviewed evidence. Proposed replacements: endothelin receptor signaling pathway Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0007186 G protein-coupled receptor signaling pathway	ISO GO_REF:0000119	MODIFY	Summary: G protein-coupled receptor signaling pathway captures the right general biology for Edn1, but a more specific GO term is available. Reason: The current term is too broad or less precise than endothelin receptor signaling pathway for this gene. Replace with endothelin receptor signaling pathway to align the annotation with the reviewed evidence. Proposed replacements: endothelin receptor signaling pathway Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0007267 cell-cell signaling	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: cell-cell signaling is biologically consistent with secreted paracrine Edn1 ligand activity but is less specific than endothelin receptor signaling. Reason: Edn1 is a secreted peptide ligand that mediates receptor-dependent communication between cells; retain the broad signaling term as non-core while preferring endothelin receptor signaling and receptor ligand terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB.
GO:0008284 positive regulation of cell population proliferation	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of cell population proliferation is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0010460 positive regulation of heart rate	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of heart rate is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: PMID:23933587 controlling the fate of neural crest cells through a Dlx5/Dlx6-independent mechanism
GO:0010613 positive regulation of cardiac muscle hypertrophy	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of cardiac muscle hypertrophy is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0010629 negative regulation of gene expression	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: negative regulation of gene expression is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0014824 artery smooth muscle contraction	ISO GO_REF:0000119	ACCEPT	Summary: artery smooth muscle contraction is a direct vascular output of endothelin-1 receptor signaling. Reason: ET-1 is a vasoactive peptide ligand whose ETA/EDNRA signaling in vascular smooth muscle drives vasoconstriction through PLC/calcium signaling, making this term consistent with the curated vascular contraction function. Supporting Evidence: file:mouse/Edn1/Edn1-deep-research-falcon.md ETA (EDNRA/ETAR): classically enriched on vascular smooth muscle cells (VSMCs) and mediates potent, sustained vasoconstriction and growth/remodeling programs.
GO:0014826 vein smooth muscle contraction	ISO GO_REF:0000119	ACCEPT	Summary: vein smooth muscle contraction is biologically consistent with the curated synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000119). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0019722 calcium-mediated signaling	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: calcium-mediated signaling is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0023019 signal transduction involved in regulation of gene expression	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: signal transduction involved in regulation of gene expression is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0030072 peptide hormone secretion	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: peptide hormone secretion is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0030185 nitric oxide transport	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: nitric oxide transport is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0030335 positive regulation of cell migration	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of cell migration is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0031394 positive regulation of prostaglandin biosynthetic process	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: positive regulation of prostaglandin biosynthetic process is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0031707 endothelin A receptor binding	ISO GO_REF:0000119	ACCEPT	Summary: endothelin A receptor binding is biologically consistent with the curated synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000119). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon reports that mature ET-1 signals through ETA/EDNRA receptors, supporting endothelin A receptor binding.
GO:0031708 endothelin B receptor binding	ISO GO_REF:0000119	ACCEPT	Summary: endothelin B receptor binding is biologically consistent with the curated synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000119). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon reports that mature ET-1 signals through ETB/EDNRB receptors, supporting endothelin B receptor binding.
GO:0042310 vasoconstriction	ISO GO_REF:0000119	ACCEPT	Summary: vasoconstriction is biologically consistent with the curated synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000119). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0043410 positive regulation of MAPK cascade	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of MAPK cascade is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: phosphatidylinositol 3-kinase/protein kinase B signal transduction is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0045793 positive regulation of cell size	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of cell size is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0045840 positive regulation of mitotic nuclear division	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of mitotic nuclear division is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0045944 positive regulation of transcription by RNA polymerase II	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of transcription by RNA polymerase II is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0046330 positive regulation of JNK cascade	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of JNK cascade is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0046887 positive regulation of hormone secretion	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of hormone secretion is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0048661 positive regulation of smooth muscle cell proliferation	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of smooth muscle cell proliferation is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0050850 positive regulation of calcium-mediated signaling	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of calcium-mediated signaling is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0051248 negative regulation of protein metabolic process	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: negative regulation of protein metabolic process is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0060298 positive regulation of sarcomere organization	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of sarcomere organization is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0061051 positive regulation of cell growth involved in cardiac muscle cell development	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of cell growth involved in cardiac muscle cell development is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: PMID:15110048 ET-1/EdnrA signaling may contribute to the dorsoventral axis patterning of the branchial arch system
GO:0070101 positive regulation of chemokine-mediated signaling pathway	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of chemokine-mediated signaling pathway is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0086100 endothelin receptor signaling pathway	ISO GO_REF:0000119	ACCEPT	Summary: endothelin receptor signaling pathway is biologically consistent with the curated synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000119). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core receptor binding and signaling: Endothelin stimulates high-affinity receptor binding and phospholipase C signaling in fibroblasts; the abstract reports that endothelin "specifically binds to a single class of high affinity receptors" and "stimulates phospholipase C with the production of second messengers inositol trisphosphate and 1,2-diacylglycerol." file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon summarizes the canonical endothelin receptor pathway: ET-1 activates ETA/ETB GPCRs with Gq/11-PLC-calcium/PKC and other downstream signaling.
GO:0160195 negative regulation of phospholipase C/protein kinase C signal transduction	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: negative regulation of phospholipase C/protein kinase C signal transduction is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0001821 histamine secretion	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: histamine secretion is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0005615 extracellular space	ISO GO_REF:0000096	ACCEPT	Summary: extracellular space is biologically consistent with the curated synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000096). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon states that ET-1 functions as an extracellular ligand produced by endothelial and epithelial cells.
GO:0007204 positive regulation of cytosolic calcium ion concentration	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: positive regulation of cytosolic calcium ion concentration is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0008217 regulation of blood pressure	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: regulation of blood pressure is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0008284 positive regulation of cell population proliferation	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: positive regulation of cell population proliferation is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0010629 negative regulation of gene expression	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: negative regulation of gene expression is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0014824 artery smooth muscle contraction	ISO GO_REF:0000096	ACCEPT	Summary: artery smooth muscle contraction is a direct vascular output of endothelin-1 receptor signaling. Reason: ET-1 is a vasoactive peptide ligand whose ETA/EDNRA signaling in vascular smooth muscle drives vasoconstriction through PLC/calcium signaling, making this term consistent with the curated vascular contraction function. Supporting Evidence: file:mouse/Edn1/Edn1-deep-research-falcon.md ETA (EDNRA/ETAR): classically enriched on vascular smooth muscle cells (VSMCs) and mediates potent, sustained vasoconstriction and growth/remodeling programs.
GO:0031707 endothelin A receptor binding	ISO GO_REF:0000096	ACCEPT	Summary: endothelin A receptor binding is biologically consistent with the curated synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000096). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon reports that mature ET-1 signals through ETA/EDNRA receptors, supporting endothelin A receptor binding.
GO:0031708 endothelin B receptor binding	ISO GO_REF:0000096	ACCEPT	Summary: endothelin B receptor binding is biologically consistent with the curated synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000096). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon reports that mature ET-1 signals through ETB/EDNRB receptors, supporting endothelin B receptor binding.
GO:0032308 positive regulation of prostaglandin secretion	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: positive regulation of prostaglandin secretion is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0033093 Weibel-Palade body	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Weibel-Palade body localization reflects endothelial regulated storage/secretion of ET-1 precursor-processing components. Reason: This supports regulated endothelial storage and secretion of ET-1, but remains a localization/trafficking context rather than the core ligand signaling role. Supporting Evidence: file:mouse/Edn1/Edn1-deep-research-falcon.md ET-1 precursors and processing components can be stored in endothelial secretory vesicles, particularly Weibel-Palade bodies, with reported co-localization of pro-ET-1 and ECE-1.
GO:0034392 negative regulation of smooth muscle cell apoptotic process	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: negative regulation of smooth muscle cell apoptotic process is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0035556 intracellular signal transduction	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: intracellular signal transduction is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0042045 epithelial fluid transport	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: epithelial fluid transport is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0042310 vasoconstriction	ISO GO_REF:0000096	ACCEPT	Summary: vasoconstriction is biologically consistent with the curated synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000096). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0042482 positive regulation of odontogenesis	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: positive regulation of odontogenesis is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0042554 superoxide anion generation	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: superoxide anion generation is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0045178 basal part of cell	ISO GO_REF:0000096	UNDECIDED	Summary: The local evidence supports Edn1 as a secreted ligand but does not verify this specific basal-cell localization. Reason: The generic secreted-ligand evidence and Weibel-Palade storage model do not establish a basal part of cell annotation for Edn1.
GO:0045944 positive regulation of transcription by RNA polymerase II	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: positive regulation of transcription by RNA polymerase II is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0045987 positive regulation of smooth muscle contraction	ISO GO_REF:0000096	ACCEPT	Summary: positive regulation of smooth muscle contraction is biologically consistent with the curated synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000096). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure." file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon identifies ET-1 as a potent vasoconstrictor whose ETA signaling in vascular smooth muscle promotes sustained contraction.
GO:0046888 negative regulation of hormone secretion	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: negative regulation of hormone secretion is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0048237 rough endoplasmic reticulum lumen	ISO GO_REF:0000096	UNDECIDED	Summary: The local evidence supports Edn1 as a secreted peptide precursor, but does not verify a rough endoplasmic reticulum lumen localization. Reason: Secretory-protein biology alone is not enough to retain this specific automated cellular-component annotation without direct localization evidence.
GO:0051899 membrane depolarization	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: membrane depolarization is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0090023 positive regulation of neutrophil chemotaxis	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: positive regulation of neutrophil chemotaxis is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:1901224 positive regulation of non-canonical NF-kappaB signal transduction	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: positive regulation of non-canonical NF-kappaB signal transduction is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:1904707 positive regulation of vascular associated smooth muscle cell proliferation	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: positive regulation of vascular associated smooth muscle cell proliferation is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:1900182 positive regulation of protein localization to nucleus	IMP PMID:21525433 Endothelin-1 contributes to increased NFATc3 activation by c...	MARK AS OVER ANNOTATED	Summary: positive regulation of protein localization to nucleus is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:1905653 positive regulation of artery morphogenesis	IMP PMID:20495147 NFATc3 contributes to intermittent hypoxia-induced arterial ...	KEEP AS NON CORE	Summary: positive regulation of artery morphogenesis is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: PMID:9671575 dHAND and the related gene, eHAND, are downregulated in the branchial and aortic arches of Edn1-null embryos.
GO:0005615 extracellular space	IDA PMID:24722437 Direct action of endothelin-1 on podocytes promotes diabetic...	ACCEPT	Summary: extracellular space is biologically consistent with the curated synthesis for Edn1 and is supported by IDA evidence (PMID:24722437). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon states that ET-1 functions as an extracellular ligand produced by endothelial and epithelial cells.
GO:0048018 receptor ligand activity	IDA PMID:24722437 Direct action of endothelin-1 on podocytes promotes diabetic...	ACCEPT	Summary: receptor ligand activity is biologically consistent with the curated synthesis for Edn1 and is supported by IDA evidence (PMID:24722437). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB.
GO:0086100 endothelin receptor signaling pathway	IDA PMID:24722437 Direct action of endothelin-1 on podocytes promotes diabetic...	ACCEPT	Summary: endothelin receptor signaling pathway is biologically consistent with the curated synthesis for Edn1 and is supported by IDA evidence (PMID:24722437). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core receptor binding and signaling: Endothelin stimulates high-affinity receptor binding and phospholipase C signaling in fibroblasts; the abstract reports that endothelin "specifically binds to a single class of high affinity receptors" and "stimulates phospholipase C with the production of second messengers inositol trisphosphate and 1,2-diacylglycerol." file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon summarizes the canonical endothelin receptor pathway: ET-1 activates ETA/ETB GPCRs with Gq/11-PLC-calcium/PKC and other downstream signaling.
GO:0003015 heart process	IMP PMID:25197047 Essential role of sympathetic endothelin A receptors for adv...	KEEP AS NON CORE	Summary: heart process is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: PMID:8152482 have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs.
GO:0003015 heart process	IMP PMID:31219639 Cdc42 activation by endothelin regulates neural crest cell m...	KEEP AS NON CORE	Summary: heart process is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: PMID:23933587 Edn1 and Ednra knock-out mice demonstrate abnormalities in pharyngeal arch artery patterning
GO:0007411 axon guidance	IMP PMID:30735130 Venous endothelin modulates responsiveness of cardiac sympat...	KEEP AS NON CORE	Summary: axon guidance is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Sympathetic axon guidance: Venous endothelin-1 is a direct guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin controls growth and guidance of the STG axons to the heart."
GO:0008217 regulation of blood pressure	IMP PMID:16868309 Collecting duct-specific knockout of the endothelin B recept...	KEEP AS NON CORE	Summary: regulation of blood pressure is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0048675 axon extension	IDA PMID:18401410 Endothelins are vascular-derived axonal guidance cues for de...	KEEP AS NON CORE	Summary: axon extension is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Sympathetic axon guidance: Venous endothelin-1 is a direct guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin controls growth and guidance of the STG axons to the heart."
GO:0000165 MAPK cascade	IDA PMID:19111534 Paracrine regulation of the resumption of oocyte meiosis by ...	MARK AS OVER ANNOTATED	Summary: MAPK cascade is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0000165 MAPK cascade	IMP PMID:19111534 Paracrine regulation of the resumption of oocyte meiosis by ...	MARK AS OVER ANNOTATED	Summary: MAPK cascade is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0044751 cellular response to human chorionic gonadotropin stimulus	IDA PMID:19111534 Paracrine regulation of the resumption of oocyte meiosis by ...	KEEP AS NON CORE	Summary: cellular response to human chorionic gonadotropin stimulus is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: PMID:19111534 The stimulatory effect of hCG on GVBD was partially blocked by the same antagonist.
GO:0071372 cellular response to follicle-stimulating hormone stimulus	IDA PMID:19111534 Paracrine regulation of the resumption of oocyte meiosis by ...	UNDECIDED	Summary: The cited oocyte paper supports LH/hCG-responsive Edn1 signaling, but does not directly establish a follicle-stimulating hormone response. Reason: Retaining this FSH-specific annotation requires evidence beyond the LH/hCG and ET-1/EDNRA oocyte-maturation results in the available citation.
GO:0071373 cellular response to luteinizing hormone stimulus	IDA PMID:19111534 Paracrine regulation of the resumption of oocyte meiosis by ...	KEEP AS NON CORE	Summary: cellular response to luteinizing hormone stimulus is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: PMID:19111534 in response to the preovulatory luteinizing hormone (LH)/human chorionic gonadotropin (hCG) stimulation.
GO:1903537 meiotic cell cycle process involved in oocyte maturation	IDA PMID:19111534 Paracrine regulation of the resumption of oocyte meiosis by ...	KEEP AS NON CORE	Summary: meiotic cell cycle process involved in oocyte maturation is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: PMID:19111534 treatment with endothelin-1 promoted oocyte GVBD.
GO:0010467 gene expression	IDA PMID:20929948 Endothelin receptor type A expression defines a distinct car...	KEEP AS NON CORE	Summary: gene expression is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0070371 ERK1 and ERK2 cascade	IDA PMID:20929948 Endothelin receptor type A expression defines a distinct car...	KEEP AS NON CORE	Summary: ERK1 and ERK2 cascade is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0008217 regulation of blood pressure	IMP PMID:20516397 Low blood pressure in endothelial cell-specific endothelin 1...	KEEP AS NON CORE	Summary: regulation of blood pressure is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0010467 gene expression	IMP PMID:20516397 Low blood pressure in endothelial cell-specific endothelin 1...	KEEP AS NON CORE	Summary: gene expression is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0001569 branching involved in blood vessel morphogenesis	IMP PMID:23933587 Endothelin regulates neural crest deployment and fate to for...	KEEP AS NON CORE	Summary: branching involved in blood vessel morphogenesis is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: PMID:23933587 Edn1/Ednra signaling is involved in pharyngeal artery development by controlling the fate of neural crest cells
GO:0014033 neural crest cell differentiation	IMP PMID:23933587 Endothelin regulates neural crest deployment and fate to for...	KEEP AS NON CORE	Summary: neural crest cell differentiation is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: PMID:23933587 controlling the fate of neural crest cells through a Dlx5/Dlx6-independent mechanism
GO:0014034 neural crest cell fate commitment	IMP PMID:23933587 Endothelin regulates neural crest deployment and fate to for...	KEEP AS NON CORE	Summary: neural crest cell fate commitment is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: PMID:23933587 Edn1 and Ednra knock-out mice demonstrate abnormalities in pharyngeal arch artery patterning
GO:0061626 pharyngeal arch artery morphogenesis	IMP PMID:23933587 Endothelin regulates neural crest deployment and fate to for...	KEEP AS NON CORE	Summary: pharyngeal arch artery morphogenesis is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: PMID:23933587 Edn1 and Ednra knock-out mice demonstrate abnormalities in pharyngeal arch artery patterning
GO:0070294 renal sodium ion absorption	IDA PMID:23698114 Endothelin-1 inhibits sodium reabsorption by ET(A) and ET(B)...	KEEP AS NON CORE	Summary: renal sodium ion absorption is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Kidney and podocyte disease evidence: Endothelin-1 stimulation of primary mouse podocytes "elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)" and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.
GO:0007005 mitochondrion organization	IDA PMID:27899487 Glomerular Endothelial Mitochondrial Dysfunction Is Essentia...	KEEP AS NON CORE	Summary: mitochondrion organization is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0030878 thyroid gland development	IMP PMID:26506449 Postotic and preotic cranial neural crest cells differently ...	KEEP AS NON CORE	Summary: thyroid gland development is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: PMID:15110048 ET-1/EdnrA signaling may contribute to the dorsoventral axis patterning of the branchial arch system
GO:0001975 response to amphetamine	IMP PMID:24875861 Venous endothelin guides sympathetic innervation of the deve...	MARK AS OVER ANNOTATED	Summary: response to amphetamine is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0003253 cardiac neural crest cell migration involved in outflow tract morphogenesis	IDA PMID:31219639 Cdc42 activation by endothelin regulates neural crest cell m...	KEEP AS NON CORE	Summary: cardiac neural crest cell migration involved in outflow tract morphogenesis is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: PMID:31219639 Cdc42 is part of the signaling pathway activated by endothelin specifically in OFT CNCC to control their migration.
GO:0003357 noradrenergic neuron differentiation	IMP PMID:24875861 Venous endothelin guides sympathetic innervation of the deve...	KEEP AS NON CORE	Summary: noradrenergic neuron differentiation is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Sympathetic axon guidance: Venous endothelin-1 is a direct guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin controls growth and guidance of the STG axons to the heart."
GO:0006468 protein phosphorylation	IDA PMID:31219639 Cdc42 activation by endothelin regulates neural crest cell m...	MODIFY	Summary: protein phosphorylation captures the right general biology for Edn1, but a more specific GO term is available. Reason: The current term is too broad or less precise than endothelin receptor signaling pathway for this gene. Replace with endothelin receptor signaling pathway to align the annotation with the reviewed evidence. Proposed replacements: endothelin receptor signaling pathway Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0007507 heart development	IMP PMID:24875861 Venous endothelin guides sympathetic innervation of the deve...	KEEP AS NON CORE	Summary: heart development is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Cardiovascular development: Edn1-/- mice have "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract."
GO:0010467 gene expression	IMP PMID:30735130 Venous endothelin modulates responsiveness of cardiac sympat...	KEEP AS NON CORE	Summary: gene expression is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0031175 neuron projection development	IDA PMID:24875861 Venous endothelin guides sympathetic innervation of the deve...	KEEP AS NON CORE	Summary: neuron projection development is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Sympathetic axon guidance: Venous endothelin-1 is a direct guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin controls growth and guidance of the STG axons to the heart."
GO:0035050 embryonic heart tube development	IMP PMID:24875861 Venous endothelin guides sympathetic innervation of the deve...	KEEP AS NON CORE	Summary: embryonic heart tube development is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Cardiovascular development: Edn1-/- mice have "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract."
GO:0035050 embryonic heart tube development	IMP PMID:30735130 Venous endothelin modulates responsiveness of cardiac sympat...	KEEP AS NON CORE	Summary: embryonic heart tube development is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Cardiovascular development: Edn1-/- mice have "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract."
GO:0035050 embryonic heart tube development	IMP PMID:31219639 Cdc42 activation by endothelin regulates neural crest cell m...	KEEP AS NON CORE	Summary: embryonic heart tube development is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Cardiovascular development: Edn1-/- mice have "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract."
GO:0060385 axonogenesis involved in innervation	IMP PMID:24875861 Venous endothelin guides sympathetic innervation of the deve...	KEEP AS NON CORE	Summary: axonogenesis involved in innervation is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Sympathetic axon guidance: Venous endothelin-1 is a direct guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin controls growth and guidance of the STG axons to the heart."
GO:0060385 axonogenesis involved in innervation	IMP PMID:30735130 Venous endothelin modulates responsiveness of cardiac sympat...	KEEP AS NON CORE	Summary: axonogenesis involved in innervation is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Sympathetic axon guidance: Venous endothelin-1 is a direct guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin controls growth and guidance of the STG axons to the heart."
GO:0071526 semaphorin-plexin signaling pathway	IMP PMID:30735130 Venous endothelin modulates responsiveness of cardiac sympat...	KEEP AS NON CORE	Summary: semaphorin-plexin signaling pathway is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0086100 endothelin receptor signaling pathway	IDA PMID:31219639 Cdc42 activation by endothelin regulates neural crest cell m...	ACCEPT	Summary: endothelin receptor signaling pathway is biologically consistent with the curated synthesis for Edn1 and is supported by IDA evidence (PMID:31219639). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core receptor binding and signaling: Endothelin stimulates high-affinity receptor binding and phospholipase C signaling in fibroblasts; the abstract reports that endothelin "specifically binds to a single class of high affinity receptors" and "stimulates phospholipase C with the production of second messengers inositol trisphosphate and 1,2-diacylglycerol." file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon summarizes the canonical endothelin receptor pathway: ET-1 activates ETA/ETB GPCRs with Gq/11-PLC-calcium/PKC and other downstream signaling.
GO:0097492 sympathetic neuron axon guidance	IMP PMID:30735130 Venous endothelin modulates responsiveness of cardiac sympat...	KEEP AS NON CORE	Summary: sympathetic neuron axon guidance is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Sympathetic axon guidance: Venous endothelin-1 is a direct guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin controls growth and guidance of the STG axons to the heart."
GO:0003094 glomerular filtration	IDA PMID:31402170 Endothelin receptor-A mediates degradation of the glomerular...	KEEP AS NON CORE	Summary: glomerular filtration is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Kidney and podocyte disease evidence: Endothelin-1 stimulation of primary mouse podocytes "elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)" and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.
GO:0006366 transcription by RNA polymerase II	IDA PMID:27026367 Endothelin-1 Induces Proteinuria by Heparanase-Mediated Disr...	MARK AS OVER ANNOTATED	Summary: transcription by RNA polymerase II is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0006874 intracellular calcium ion homeostasis	ISO PMID:30990108 ET(A)R and protein kinase A pathway mediate ET-1 sensitizati...	KEEP AS NON CORE	Summary: intracellular calcium ion homeostasis is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Kidney and podocyte disease evidence: Endothelin-1 stimulation of primary mouse podocytes "elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)" and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.
GO:0006874 intracellular calcium ion homeostasis	IDA PMID:30990108 ET(A)R and protein kinase A pathway mediate ET-1 sensitizati...	KEEP AS NON CORE	Summary: intracellular calcium ion homeostasis is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Kidney and podocyte disease evidence: Endothelin-1 stimulation of primary mouse podocytes "elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)" and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.
GO:0010467 gene expression	IDA PMID:24722437 Direct action of endothelin-1 on podocytes promotes diabetic...	KEEP AS NON CORE	Summary: gene expression is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0060070 canonical Wnt signaling pathway	IDA PMID:24722437 Direct action of endothelin-1 on podocytes promotes diabetic...	KEEP AS NON CORE	Summary: canonical Wnt signaling pathway is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0070301 cellular response to hydrogen peroxide	ISO PMID:30990108 ET(A)R and protein kinase A pathway mediate ET-1 sensitizati...	MARK AS OVER ANNOTATED	Summary: cellular response to hydrogen peroxide is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0070588 calcium ion transmembrane transport	IDA PMID:24722437 Direct action of endothelin-1 on podocytes promotes diabetic...	KEEP AS NON CORE	Summary: calcium ion transmembrane transport is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0072011 glomerular endothelium development	IDA PMID:31402170 Endothelin receptor-A mediates degradation of the glomerular...	KEEP AS NON CORE	Summary: glomerular endothelium development is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Kidney and podocyte disease evidence: Endothelin-1 stimulation of primary mouse podocytes "elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)" and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.
GO:0072112 podocyte differentiation	IDA PMID:31402170 Endothelin receptor-A mediates degradation of the glomerular...	KEEP AS NON CORE	Summary: podocyte differentiation is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Kidney and podocyte disease evidence: Endothelin-1 stimulation of primary mouse podocytes "elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)" and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.
GO:0097237 cellular response to toxic substance	ISO PMID:30990108 ET(A)R and protein kinase A pathway mediate ET-1 sensitizati...	MARK AS OVER ANNOTATED	Summary: cellular response to toxic substance is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0097237 cellular response to toxic substance	IDA PMID:30990108 ET(A)R and protein kinase A pathway mediate ET-1 sensitizati...	MARK AS OVER ANNOTATED	Summary: cellular response to toxic substance is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0097237 cellular response to toxic substance	IMP PMID:30990108 ET(A)R and protein kinase A pathway mediate ET-1 sensitizati...	MARK AS OVER ANNOTATED	Summary: cellular response to toxic substance is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0141156 cAMP/PKA signal transduction	ISO PMID:30990108 ET(A)R and protein kinase A pathway mediate ET-1 sensitizati...	MARK AS OVER ANNOTATED	Summary: cAMP/PKA signal transduction is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:2001259 positive regulation of cation channel activity	ISO PMID:30990108 ET(A)R and protein kinase A pathway mediate ET-1 sensitizati...	MARK AS OVER ANNOTATED	Summary: positive regulation of cation channel activity is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0031583 phospholipase D-activating G protein-coupled receptor signaling pathway	IDA PMID:8978712 Endothelin stimulates phospholipase D in striatal astrocytes...	KEEP AS NON CORE	Summary: phospholipase D-activating G protein-coupled receptor signaling pathway is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core receptor binding and signaling: Endothelin stimulates high-affinity receptor binding and phospholipase C signaling in fibroblasts; the abstract reports that endothelin "specifically binds to a single class of high affinity receptors" and "stimulates phospholipase C with the production of second messengers inositol trisphosphate and 1,2-diacylglycerol."
GO:0009953 dorsal/ventral pattern formation	IMP PMID:15110048 Endothelin-1 regulates the dorsoventral branchial arch patte...	KEEP AS NON CORE	Summary: dorsal/ventral pattern formation is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: PMID:15110048 ET-1/EdnrA signaling may contribute to the dorsoventral axis patterning of the branchial arch system
GO:0086100 endothelin receptor signaling pathway	ISS GO_REF:0000024	ACCEPT	Summary: endothelin receptor signaling pathway is biologically consistent with the curated synthesis for Edn1 and is supported by ISS evidence (GO_REF:0000024). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core receptor binding and signaling: Endothelin stimulates high-affinity receptor binding and phospholipase C signaling in fibroblasts; the abstract reports that endothelin "specifically binds to a single class of high affinity receptors" and "stimulates phospholipase C with the production of second messengers inositol trisphosphate and 1,2-diacylglycerol." file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon summarizes the canonical endothelin receptor pathway: ET-1 activates ETA/ETB GPCRs with Gq/11-PLC-calcium/PKC and other downstream signaling.
GO:0010827 regulation of D-glucose transmembrane transport	IDA PMID:11546805 beta -Arrestin-mediated recruitment of the Src family kinase...	KEEP AS NON CORE	Summary: regulation of D-glucose transmembrane transport is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	IGI PMID:15632412 Collecting duct-specific knockout of endothelin-1 alters vas...	KEEP AS NON CORE	Summary: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core receptor binding and signaling: Endothelin stimulates high-affinity receptor binding and phospholipase C signaling in fibroblasts; the abstract reports that endothelin "specifically binds to a single class of high affinity receptors" and "stimulates phospholipase C with the production of second messengers inositol trisphosphate and 1,2-diacylglycerol."
GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	IDA PMID:2542249 A novel vasoactive peptide endothelin stimulates mitogenesis...	KEEP AS NON CORE	Summary: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core receptor binding and signaling: Endothelin stimulates high-affinity receptor binding and phospholipase C signaling in fibroblasts; the abstract reports that endothelin "specifically binds to a single class of high affinity receptors" and "stimulates phospholipase C with the production of second messengers inositol trisphosphate and 1,2-diacylglycerol."
GO:0035810 positive regulation of urine volume	IMP PMID:15632412 Collecting duct-specific knockout of endothelin-1 alters vas...	KEEP AS NON CORE	Summary: positive regulation of urine volume is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0035810 positive regulation of urine volume	IGI PMID:15632412 Collecting duct-specific knockout of endothelin-1 alters vas...	KEEP AS NON CORE	Summary: positive regulation of urine volume is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0035815 positive regulation of renal sodium excretion	IMP PMID:15314687 Collecting duct-specific knockout of endothelin-1 causes hyp...	KEEP AS NON CORE	Summary: positive regulation of renal sodium excretion is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0006885 regulation of pH	IDA PMID:11413164 Endothelin-1/endothelin-B receptor-mediated increases in NHE...	KEEP AS NON CORE	Summary: regulation of pH is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0001501 skeletal system development	IMP PMID:8152482 Elevated blood pressure and craniofacial abnormalities in mi...	KEEP AS NON CORE	Summary: skeletal system development is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Cardiovascular development: Edn1-/- mice have "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract."
GO:0001569 branching involved in blood vessel morphogenesis	IMP PMID:7615798 Aortic arch malformations and ventricular septal defect in m...	KEEP AS NON CORE	Summary: branching involved in blood vessel morphogenesis is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Cardiovascular development: Edn1-/- mice have "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract."
GO:0001666 response to hypoxia	IMP PMID:8764295 Impaired ventilatory responses to hypoxia and hypercapnia in...	KEEP AS NON CORE	Summary: response to hypoxia is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0005102 signaling receptor binding	IDA PMID:2542249 A novel vasoactive peptide endothelin stimulates mitogenesis...	MODIFY	Summary: signaling receptor binding captures the right general biology for Edn1, but a more specific GO term is available. Reason: The current term is too broad or less precise than receptor ligand activity for this gene. Replace with receptor ligand activity to align the annotation with the reviewed evidence. Proposed replacements: receptor ligand activity Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB.
GO:0005102 signaling receptor binding	IDA PMID:8680799 Developmental changes in cerebellar endothelin-1 receptors i...	MODIFY	Summary: signaling receptor binding captures the right general biology for Edn1, but a more specific GO term is available. Reason: The current term is too broad or less precise than receptor ligand activity for this gene. Replace with receptor ligand activity to align the annotation with the reviewed evidence. Proposed replacements: receptor ligand activity Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB.
GO:0007200 phospholipase C-activating G protein-coupled receptor signaling pathway	IDA PMID:2542249 A novel vasoactive peptide endothelin stimulates mitogenesis...	MODIFY	Summary: phospholipase C-activating G protein-coupled receptor signaling pathway captures the right general biology for Edn1, but a more specific GO term is available. Reason: The current term is too broad or less precise than endothelin receptor signaling pathway for this gene. Replace with endothelin receptor signaling pathway to align the annotation with the reviewed evidence. Proposed replacements: endothelin receptor signaling pathway Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core receptor binding and signaling: Endothelin stimulates high-affinity receptor binding and phospholipase C signaling in fibroblasts; the abstract reports that endothelin "specifically binds to a single class of high affinity receptors" and "stimulates phospholipase C with the production of second messengers inositol trisphosphate and 1,2-diacylglycerol."
GO:0007507 heart development	IMP PMID:7615798 Aortic arch malformations and ventricular septal defect in m...	KEEP AS NON CORE	Summary: heart development is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Cardiovascular development: Edn1-/- mice have "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract."
GO:0008217 regulation of blood pressure	IMP PMID:8152482 Elevated blood pressure and craniofacial abnormalities in mi...	KEEP AS NON CORE	Summary: regulation of blood pressure is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0008284 positive regulation of cell population proliferation	IDA PMID:2542249 A novel vasoactive peptide endothelin stimulates mitogenesis...	MARK AS OVER ANNOTATED	Summary: positive regulation of cell population proliferation is related to reported Edn1 biology only as a broad downstream readout or generic interaction term. Reason: This overstates the direct role of the gene product; the curated model is better captured by the specific receptor/ligand, pathway, and supported non-core phenotype terms. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0014032 neural crest cell development	IMP PMID:9671575 A signaling cascade involving endothelin-1, dHAND and msx1 r...	KEEP AS NON CORE	Summary: neural crest cell development is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: PMID:9671575 A signaling cascade involving endothelin-1, dHAND and msx1 regulates development of neural-crest-derived branchial arch mesenchyme.
GO:0042474 middle ear morphogenesis	IMP PMID:8152482 Elevated blood pressure and craniofacial abnormalities in mi...	UNDECIDED	Summary: The available local evidence supports pharyngeal-arch-derived craniofacial abnormalities but does not directly verify middle ear morphogenesis. Reason: Retaining this specific developmental annotation requires direct middle-ear evidence rather than generic pharyngeal arch or cardiovascular phenotype support.
GO:0043179 rhythmic excitation	IMP PMID:8764295 Impaired ventilatory responses to hypoxia and hypercapnia in...	KEEP AS NON CORE	Summary: rhythmic excitation is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0045987 positive regulation of smooth muscle contraction	IDA PMID:8010105 Effects of endothelin-1 on isolated uterine horns in estroge...	ACCEPT	Summary: positive regulation of smooth muscle contraction is biologically consistent with the curated synthesis for Edn1 and is supported by IDA evidence (PMID:8010105). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure." file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon identifies ET-1 as a potent vasoconstrictor whose ETA signaling in vascular smooth muscle promotes sustained contraction.
GO:0048514 blood vessel morphogenesis	IMP PMID:7615798 Aortic arch malformations and ventricular septal defect in m...	KEEP AS NON CORE	Summary: blood vessel morphogenesis is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Cardiovascular development: Edn1-/- mice have "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract."
GO:0051216 cartilage development	IMP PMID:8152482 Elevated blood pressure and craniofacial abnormalities in mi...	KEEP AS NON CORE	Summary: cartilage development is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Cardiovascular development: Edn1-/- mice have "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract."
GO:0001701 in utero embryonic development	IMP PMID:15327783 Temporal requirement of signaling cascade involving endothel...	KEEP AS NON CORE	Summary: in utero embryonic development is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Cardiovascular development: Edn1-/- mice have "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract."
GO:0005615 extracellular space	IDA PMID:15314687 Collecting duct-specific knockout of endothelin-1 causes hyp...	ACCEPT	Summary: extracellular space is biologically consistent with the curated synthesis for Edn1 and is supported by IDA evidence (PMID:15314687). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon states that ET-1 functions as an extracellular ligand produced by endothelial and epithelial cells.
GO:0007589 body fluid secretion	IMP PMID:15314687 Collecting duct-specific knockout of endothelin-1 causes hyp...	KEEP AS NON CORE	Summary: body fluid secretion is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0008217 regulation of blood pressure	IMP PMID:15314687 Collecting duct-specific knockout of endothelin-1 causes hyp...	KEEP AS NON CORE	Summary: regulation of blood pressure is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0014032 neural crest cell development	IMP PMID:15327783 Temporal requirement of signaling cascade involving endothel...	KEEP AS NON CORE	Summary: neural crest cell development is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Cardiovascular development: Edn1-/- mice have "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract."
GO:0031707 endothelin A receptor binding	IPI PMID:9449664 Cranial and cardiac neural crest defects in endothelin-A rec...	ACCEPT	Summary: endothelin A receptor binding is biologically consistent with the curated synthesis for Edn1 and is supported by IPI evidence (PMID:9449664). Reason: The term matches a direct molecular function, pathway, or location/physiological output of Edn1; it is specific enough to retain without replacement. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. file:mouse/Edn1/Edn1-deep-research-falcon.md Falcon reports that mature ET-1 signals through ETA/EDNRA receptors, supporting endothelin A receptor binding.
GO:0005515 protein binding	IPI PMID:12441350 The first inner loop of endothelin receptor type B is necess...	REMOVE	Summary: protein binding is not supported as an appropriate annotation for Edn1 after review of the available mouse evidence. Reason: The term appears to reflect either an unsupported transfer, a paralog/family overreach, or a localization/process inconsistent with the curated Edn1 biology. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation.
GO:0007585 respiratory gaseous exchange by respiratory system	IMP PMID:10626068 Endothelin in the central control of cardiovascular and resp...	KEEP AS NON CORE	Summary: respiratory gaseous exchange by respiratory system is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0008217 regulation of blood pressure	IMP PMID:10626068 Endothelin in the central control of cardiovascular and resp...	KEEP AS NON CORE	Summary: regulation of blood pressure is supported for Edn1 in a tissue, developmental, trafficking, or disease-model context, but it is not the core molecular role. Reason: This annotation captures a real downstream or context-specific consequence of Edn1 activity. It should be retained as non-core so it does not obscure the primary receptor/ligand signaling function. Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."
GO:0007186 G protein-coupled receptor signaling pathway	TAS PMID:11546805 beta -Arrestin-mediated recruitment of the Src family kinase...	MODIFY	Summary: G protein-coupled receptor signaling pathway captures the right general biology for Edn1, but a more specific GO term is available. Reason: The current term is too broad or less precise than endothelin receptor signaling pathway for this gene. Replace with endothelin receptor signaling pathway to align the annotation with the reviewed evidence. Proposed replacements: endothelin receptor signaling pathway Supporting Evidence: file:mouse/Edn1/Edn1-notes.md Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure."

Core Functions

Mature endothelin-1 is a secreted peptide receptor ligand that binds endothelin A and B receptors to activate endothelin receptor signaling and regulate vascular tone, smooth muscle contraction, and blood-pressure physiology.

Molecular Function:

receptor ligand activity

Directly Involved In:

endothelin receptor signaling pathway regulation of systemic arterial blood pressure by endothelin positive regulation of smooth muscle contraction

Cellular Locations:

extracellular space

Supporting Evidence:

file:mouse/Edn1/Edn1-notes.md
Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB.
file:mouse/Edn1/Edn1-deep-research-falcon.md
Falcon reinforces the core model that mature ET-1 is a secreted peptide ligand for ETA/EDNRA and ETB/EDNRB receptors, driving endothelin receptor signaling, vascular tone, and blood-pressure physiology.

References

file:mouse/Edn1/Edn1-notes.md

Curator notes for mouse Edn1 review

file:mouse/Edn1/Edn1-deep-research-falcon.md

Falcon deep research report for mouse Edn1

file:mouse/Edn1/Edn1-uniprot.txt

UniProtKB record for mouse Edn1

file:mouse/Edn1/Edn1-goa.tsv

QuickGO export for mouse Edn1

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:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

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: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:10626068

Endothelin in the central control of cardiovascular and respiratory functions.

PMID:11413164

Endothelin-1/endothelin-B receptor-mediated increases in NHE3 activity in chronic metabolic acidosis.

PMID:11546805

beta -Arrestin-mediated recruitment of the Src family kinase Yes mediates endothelin-1-stimulated glucose transport.

PMID:12441350

The first inner loop of endothelin receptor type B is necessary for specific coupling to Galpha 13.

PMID:15110048

Endothelin-1 regulates the dorsoventral branchial arch patterning in mice.

PMID:15314687

Collecting duct-specific knockout of endothelin-1 causes hypertension and sodium retention.

PMID:15327783

Temporal requirement of signaling cascade involving endothelin-1/endothelin receptor type A in branchial arch development.

PMID:15632412

Collecting duct-specific knockout of endothelin-1 alters vasopressin regulation of urine osmolality.

PMID:16868309

Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention.

PMID:18401410

Endothelins are vascular-derived axonal guidance cues for developing sympathetic neurons.

PMID:19111534

Paracrine regulation of the resumption of oocyte meiosis by endothelin-1.

PMID:20495147

NFATc3 contributes to intermittent hypoxia-induced arterial remodeling in mice.

PMID:20516397

Low blood pressure in endothelial cell-specific endothelin 1 knockout mice.

PMID:20929948

Endothelin receptor type A expression defines a distinct cardiac subdomain within the heart field and is later implicated in chamber myocardium formation.

PMID:21525433

Endothelin-1 contributes to increased NFATc3 activation by chronic hypoxia in pulmonary arteries.

PMID:23698114

Endothelin-1 inhibits sodium reabsorption by ET(A) and ET(B) receptors in the mouse cortical collecting duct.

PMID:23933587

Endothelin regulates neural crest deployment and fate to form great vessels through Dlx5/Dlx6-independent mechanisms.

PMID:24722437

Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis.

PMID:24875861

Venous endothelin guides sympathetic innervation of the developing mouse heart.

PMID:25197047

Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling.

PMID:2542249

A novel vasoactive peptide endothelin stimulates mitogenesis through inositol lipid turnover in Swiss 3T3 fibroblasts.

PMID:26506449

Postotic and preotic cranial neural crest cells differently contribute to thyroid development.

PMID:27026367

Endothelin-1 Induces Proteinuria by Heparanase-Mediated Disruption of the Glomerular Glycocalyx.

PMID:27899487

Glomerular Endothelial Mitochondrial Dysfunction Is Essential and Characteristic of Diabetic Kidney Disease Susceptibility.

PMID:30735130

Venous endothelin modulates responsiveness of cardiac sympathetic axons to arterial semaphorin.

PMID:30990108

ET(A)R and protein kinase A pathway mediate ET-1 sensitization of TRPA1 channel: A molecular mechanism of ET-1-induced mechanical hyperalgesia.

PMID:31219639

Cdc42 activation by endothelin regulates neural crest cell migration in the cardiac outflow tract.

PMID:31402170

Endothelin receptor-A mediates degradation of the glomerular endothelial surface layer via pathologic crosstalk between activated podocytes and glomerular endothelial cells.

PMID:7615798

Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1.

PMID:8010105

Effects of endothelin-1 on isolated uterine horns in estrogen-primed and pregnant mice.

PMID:8152482

Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1.

PMID:8680799

Developmental changes in cerebellar endothelin-1 receptors in the neurologic mouse lurcher mutant.

PMID:8764295

Impaired ventilatory responses to hypoxia and hypercapnia in mutant mice deficient in endothelin-1.

PMID:8978712

Endothelin stimulates phospholipase D in striatal astrocytes.

PMID:9449664

Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice.

PMID:9671575

A signaling cascade involving endothelin-1, dHAND and msx1 regulates development of neural-crest-derived branchial arch mesenchyme.

Suggested Experiments

Experiment: Compare Ednra- and Ednrb-dependent responses to mature ET-1 in vascular smooth muscle, podocytes, and sympathetic neurons using receptor-selective antagonists or conditional receptor knockouts.

Hypothesis: Different Edn1 GO process annotations reflect receptor- and tissue-specific deployment of the same secreted ligand.

Type: receptor-specific ligand response assay

📚 Additional Documentation

Deep Research Falcon

(Edn1-deep-research-falcon.md)

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template_file: templates/gene_research_go_focused.md
template_variables:
organism: mouse
gene_id: Edn1
gene_symbol: Edn1
uniprot_accession: P22387
protein_description: 'RecName: Full=Endothelin-1; Short=ET-1; AltName: Full=Preproendothelin-1;
Short=PPET1; Contains: RecName: Full=Big endothelin-1; Flags: Precursor;'
gene_info: Name=Edn1;
organism_full: Mus musculus (Mouse).
protein_family: Belongs to the endothelin/sarafotoxin family.
protein_domains: Endothelin. (IPR020475); Endothelin_toxin_CS. (IPR019764); Endothln-like_toxin.
(IPR001928); Endothelin (PF00322)
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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: P22387
Protein Description: RecName: Full=Endothelin-1; Short=ET-1; AltName: Full=Preproendothelin-1; Short=PPET1; Contains: RecName: Full=Big endothelin-1; Flags: Precursor;
Gene Information: Name=Edn1;
Organism (full): Mus musculus (Mouse).
Protein Family: Belongs to the endothelin/sarafotoxin family.
Key Domains: Endothelin. (IPR020475); Endothelin_toxin_CS. (IPR019764); Endothln-like_toxin. (IPR001928); Endothelin (PF00322)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "Edn1" 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 'Edn1' 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 Edn1 (gene ID: Edn1, UniProt: P22387) 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: P22387
Protein Description: RecName: Full=Endothelin-1; Short=ET-1; AltName: Full=Preproendothelin-1; Short=PPET1; Contains: RecName: Full=Big endothelin-1; Flags: Precursor;
Gene Information: Name=Edn1;
Organism (full): Mus musculus (Mouse).
Protein Family: Belongs to the endothelin/sarafotoxin family.
Key Domains: Endothelin. (IPR020475); Endothelin_toxin_CS. (IPR019764); Endothln-like_toxin. (IPR001928); Endothelin (PF00322)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "Edn1" 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 Edn1 (gene ID: Edn1, UniProt: P22387) 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: Mouse Edn1 (UniProt P22387) — functional annotation of Endothelin-1 (ET-1)

0) Target verification (critical disambiguation)

The requested target is mouse (Mus musculus) Edn1, UniProt P22387, which encodes the Endothelin-1 (ET-1) precursor (preproendothelin-1). The literature retrieved consistently defines Edn1/EDN1 as encoding preproendothelin-1, processed to big endothelin-1 and then the mature 21-aa ET-1, a secreted signaling peptide acting primarily through ETA/ETB receptors; this matches the UniProt description and endothelin/sarafotoxin family membership. (schiffrin2024endothelinsystemin pages 1-2, schiffrin2025endothelinantagonistsfor pages 1-2, patel2024comprehensiveanalysisof pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 What Edn1 encodes

Edn1 encodes a secreted peptide hormone precursor that yields the mature vasoactive peptide endothelin-1 (ET-1) (21 amino acids). ET-1 is widely regarded as one of the most potent endogenous vasoconstrictors, but also functions as a developmental morphogen in specific embryonic contexts. (schiffrin2024endothelinsystemin pages 1-2, clouthier2004understandingendothelin1function pages 1-2)

1.2 Biosynthesis and peptide processing: prepro → big ET-1 → ET-1

ET-1 is produced by stepwise proteolysis:
- The Edn1 product is synthesized as a preproendothelin-1 precursor.
- Furin/furin-like proteases cleave proendothelin to “big endothelin-1” (38–39 aa).
- Endothelin-converting enzymes (ECE-1/ECE-2) (zinc-dependent endoproteases) cleave big ET-1 to produce mature ET-1 (21 aa).
Additional proteases (e.g., MMP-2, chymase, neutral endopeptidase) can contribute to ET-1 generation or alternative intermediates in some contexts. (schiffrin2024endothelinsystemin pages 1-2, schiffrin2024endothelinsystemin pages 2-4, schiffrin2025endothelinantagonistsfor pages 1-2)

1.3 Receptors and canonical pathway definition

ET-1 signals primarily via two class A GPCRs:
- ETA (EDNRA/ETAR): classically enriched on vascular smooth muscle cells (VSMCs) and mediates potent, sustained vasoconstriction and growth/remodeling programs.
- ETB (EDNRB/ETBR): enriched on endothelial cells (among other cell types); endothelial ETB can stimulate release of vasodilators (notably NO and prostacyclin) and ETB is also described as contributing to ET-1 clearance. (schiffrin2024endothelinsystemin pages 2-4, arndt2024endothelinandthe pages 2-2, prepeliuc2025theinvolvementof pages 4-6)

2) Molecular function, signaling mechanisms, and localization

2.1 Subcellular/extracellular localization and secretion

ET-1 functions as an extracellular ligand produced predominantly by vascular endothelial cells (also by certain epithelial cells, including in kidney). In kidney tissue, ET-1 and ECE1 protein localize in vessels and glomeruli, supporting local endothelial/glomerular production and paracrine signaling. (schiffrin2024endothelinsystemin pages 1-2, patel2024comprehensiveanalysisof media f464fe7a)

A mechanistic model of endothelial packaging is that ET-1 precursors and processing components can be stored in endothelial secretory vesicles, particularly Weibel–Palade bodies, with reported co-localization of pro-ET-1 and ECE-1; this supports regulated secretion and local processing capacity near the endothelial surface. (prepeliuc2025theinvolvementof pages 4-6)

2.2 Downstream signaling pathways (ETA/ETB)

Across authoritative sources, ET receptor activation is linked to:
- Gq/11 → PLCβ → IP3/DAG → Ca2+ mobilization and PKC activation, directly promoting VSMC contraction.
- ROS generation (e.g., via NADPH oxidase) and downstream signaling contributing to vascular remodeling.
- MAPK cascade (ras–raf–MAPK/ERK) and growth factor receptor transactivation, supporting hypertrophy and remodeling.
- Additional coupling through Gi/o, Gs, G12/13 and β-arrestin–linked signaling, providing cell-type and context-specific outputs including inflammatory transcriptional programs (e.g., NF-κB-linked). (schiffrin2024endothelinsystemin pages 2-4, prepeliuc2025theinvolvementof pages 4-6, maiza2026endothelin1inthe pages 1-2)

3) In vivo physiological roles in mouse: primary functional annotation

3.1 Adult physiology: vascular tone and renal endothelin system

ET-1 is a central regulator of vasomotor tone and contributes to blood pressure regulation and vascular remodeling in physiology and disease, with receptor-specific effects (ETA largely vasoconstrictive; endothelial ETB vasodilatory via NO/prostacyclin). (schiffrin2024endothelinsystemin pages 2-4, schiffrin2025endothelinantagonistsfor pages 1-2)

In kidney, a 2024 cross-species analysis combining scRNA-seq re-analysis and immunolocalization reported that ECE1 and ET-1 are prominent in glomeruli and endothelium, and that Ece1 mRNA is enriched in endothelium; the study also highlights a key reproducibility issue: Edn1/EDN1 mRNA is often rarely detected by scRNA-seq despite clear protein immunolocalization and measurable plasma/urinary ET-1, implying transcript-level under-detection relative to peptide/protein presence. (patel2024comprehensiveanalysisof pages 1-2, patel2024comprehensiveanalysisof media f464fe7a)

3.2 Embryonic development: Edn1 as a pharyngeal-arch morphogen for craniofacial patterning

A defining mouse-specific functional role of Edn1 is as a developmental signal in the pharyngeal arches:
- Ednra (ETA) is expressed in neural crest–derived ectomesenchyme.
- ET-1 (Edn1) is expressed in the arch environment, including arch epithelium/ectoderm, pharyngeal pouch endoderm, and the paraxial mesoderm-derived arch core; ECE-1 is coexpressed at key sites.
- Loss of Ednra signaling disrupts post-migratory neural crest transcriptional programs in arches: reduced/absent expression of goosecoid, Dlx-2, Dlx-3, dHAND (Hand2), eHAND, and Barx1, while some factors (e.g., Hoxa-2, Ufd1) are unaffected, indicating pathway specificity.
- Phenotypically, loss of ET-1/ETA/ECE-1 signaling causes severe craniofacial malformations and perinatal lethality (mechanical airway compromise), with mandibular and throat defects and associated cardiovascular outflow tract defects described in the developmental literature syntheses. (clouthier2000signalingpathwayscrucial pages 1-2, clouthier2010regulationoffacial pages 6-8, clouthier2010regulationoffacial pages 2-4)

A key refinement from conditional mouse genetics is that ectodermal-derived Edn1 is required for mandibular arch patterning; a study using tissue-specific Cre drivers concluded that facial patterning defects occur only when Edn1 is inactivated in ectoderm, and that critical Edn1 function occurs in a narrow developmental window around E8.5–E9.0. (tavares2012ectodermalderivedendothelin1is pages 1-2, tavares2012ectodermalderivedendothelin1is pages 2-4)

4) Recent developments (prioritizing 2023–2024) and real-world implementations

Although Edn1 is a mouse gene, the EDN1/ET-1 pathway is intensively targeted translationally; 2023–2024 sources summarize a renewed clinical focus on endothelin pathway modulation.

4.1 Drug development and clinical implementation (endothelin pathway targeting)

A 2023 cardiovascular translational review highlights expanding strategies beyond pulmonary arterial hypertension, including precision approaches using EDN1-regulatory genetics to enrich for response and new therapeutic modalities (e.g., long-acting biologics). (abraham2023currentandfuture pages 1-4, abraham2023currentandfuture pages 7-11)

Sparsentan (dual ETA/AT1 antagonist) is reported as receiving approval in 2023 for IgA nephropathy; pooled DUET phase II data in that review reported a 44.8% reduction in urine protein-to-creatinine ratio versus 18.5% with irbesartan and partial remission rates of 28.1% vs 9.4%, respectively. (abraham2023currentandfuture pages 17-20)

A key clinical limitation of endothelin receptor antagonists is fluid retention/edema; the 2023 review cites peripheral edema in 17% of pulmonary arterial hypertension patients treated with bosentan, and discusses fluid overload as a class effect relevant to clinical management and combination strategies. (abraham2023currentandfuture pages 1-4)

4.2 Biomarkers and human tissue evidence supporting endothelin-axis targeting

A 2024 human portal vein transcriptomic study (portal hypertension vs controls) provides a contemporary example of the endothelin axis appearing among top enriched pathways, supporting interest in endothelin antagonism in portal hypertension. In portal vein samples (PH n=12; controls n=9), the authors detected 9,964 genes above background and identified 2,544 differentially expressed genes (adjusted P<0.05; fold-change >1.5), with 49 enriched pathways; the endothelin pathway ranked 10th, with EDN1 up-regulated and EDNRA down-regulated (adaptive response) and EDNRB unchanged. (owen2024microarrayanalysisdemonstrates pages 1-2)

5) Quantitative/statistical highlights from recent studies (selected)

The following extracted values summarize actionable quantitative evidence spanning genetics, pharmacology, transcriptomics, and therapeutic outcomes.

rs9349379 minor G allele frequency: 40% in the general population and 46% in the CorMicA cohort. (abraham2023currentandfuture pages 7-11)

Sparsentan in pooled DUET phase II data: 44.8% reduction in urine protein-to-creatinine ratio vs 18.5% with irbesartan; partial remission 28.1% vs 9.4%. (abraham2023currentandfuture pages 17-20)

Bosentan-associated peripheral edema in PAH: 17%. (abraham2023currentandfuture pages 1-4)

Portal vein microarray study: PH n=12 vs control n=9; ~20,800 genes measured; 9,964 detected above background; 2,544 DEGs defined by adjusted P < 0.05 and fold change > 1.5, with 548 up-regulated and 1,996 down-regulated genes; 49 enriched pathways; endothelin pathway ranked 10th. (owen2024microarrayanalysisdemonstrates pages 1-2)

Portal pressure cutoffs: normal 5-10 mmHg; HVPG >5 mmHg defines portal hypertension; HVPG >10 mmHg is associated with clinical complications. (owen2024microarrayanalysisdemonstrates pages 1-2)

Getagozumab (GMA301): Kd ~8.7 nM, IC50 ~38 nM; monkey half-life 7-10 days; human plasma half-life ~21 days. (abraham2023currentandfuture pages 7-11)

Mouse developmental time window for Edn1 mandibular arch patterning: E8.5-E9.0. (tavares2012ectodermalderivedendothelin1is pages 2-4)

Blockquote: This blockquote lists the main numerical findings extracted for the EDN1/Edn1 pathway, spanning genetics, therapeutics, transcriptomics, hemodynamic thresholds, pharmacology, and mouse developmental timing. It is useful as a compact reference for the most actionable quantitative evidence.

6) Expert opinions and analysis (authoritative synthesis)

System-level view (hypertension/CKD): A 2024 Hypertension review emphasizes ET-1 as a broadly expressed mediator with receptor-specific actions across vascular and renal beds and highlights mechanistic links to ROS, MAPK signaling, hypertrophy/remodeling, and the complexity of ETA vs ETB roles (including endothelial ETB vasodilatory signaling). (schiffrin2024endothelinsystemin pages 1-2, schiffrin2024endothelinsystemin pages 2-4)
Translational state of the field (2023): A 2023 review argues that translational research over the prior ~5 years has “reignited interest” in endothelin targeting for broader cardiovascular indications, including genotype-informed trial enrichment (e.g., EDN1 regulatory locus rs9349379), dual-mechanism small molecules, and long-acting biologics such as anti-ETA monoclonal antibodies. (abraham2023currentandfuture pages 1-4, abraham2023currentandfuture pages 7-11)
Experimental rigor note (2024 kidney analysis): A 2024 kidney-focused analysis warns that mRNA detection (scRNA-seq) may under-represent Edn1/EDN1 relative to protein localization and measurable peptide levels, recommending multi-modal validation (protein immunolocalization plus transcriptomics) for robust functional inference. (patel2024comprehensiveanalysisof pages 1-2)

7) Summary table for functional annotation (mouse Edn1)

Aspect	Key points	Representative recent sources with year and URL	Citation IDs
Gene product	Mouse Edn1 (UniProt P22387) encodes preproendothelin-1 / endothelin-1 precursor, yielding the mature 21-aa ET-1 peptide, a potent vasoactive signaling molecule.	Schiffrin & Pollock, 2024, Hypertension — https://doi.org/10.1161/hypertensionaha.123.21716; Patel et al., 2024, Bioscience Reports — https://doi.org/10.1042/bsr20240768	(schiffrin2024endothelinsystemin pages 1-2, patel2024comprehensiveanalysisof pages 1-2)
Processing	ET-1 is produced by stepwise proteolysis: precursor/proendothelin is cleaved to big ET-1 (38–39 aa), then ECE-1/ECE-2 generate mature ET-1; alternative proteases can also contribute.	Schiffrin & Pollock, 2024 — https://doi.org/10.1161/hypertensionaha.123.21716; Schiffrin, 2025 — https://doi.org/10.1042/cs20255853	(schiffrin2024endothelinsystemin pages 1-2, schiffrin2025endothelinantagonistsfor pages 1-2)
Receptors	Mature ET-1 signals through two GPCRs: ETA/EDNRA and ETB/EDNRB. ETA is the major vasoconstrictor receptor on vascular smooth muscle; endothelial ETB promotes NO/prostacyclin release and vasodilation; ETB can also contribute to ET-1 clearance.	Schiffrin & Pollock, 2024 — https://doi.org/10.1161/hypertensionaha.123.21716; Arndt et al., 2024 — https://doi.org/10.1042/cs20240426; Prepeliuc et al., 2025 — https://doi.org/10.3390/biomedicines13102480	(schiffrin2024endothelinsystemin pages 2-4, arndt2024endothelinandthe pages 2-2, prepeliuc2025theinvolvementof pages 4-6)
Signaling	Canonical downstream signaling includes Gq/11 → PLCβ → IP3/DAG → Ca2+/PKC, plus ROS generation, MAPK/ERK, and growth/remodeling pathways; ET signaling can also involve G12/13 and β-arrestin-linked signaling.	Schiffrin & Pollock, 2024 — https://doi.org/10.1161/hypertensionaha.123.21716; Prepeliuc et al., 2025 — https://doi.org/10.3390/biomedicines13102480; Maiza, 2026 — https://doi.org/10.3389/fped.2025.1718057	(schiffrin2024endothelinsystemin pages 2-4, prepeliuc2025theinvolvementof pages 4-6, maiza2026endothelin1inthe pages 1-2)
Production/localization	ET-1 is produced predominantly by vascular endothelial cells and also by some epithelial cells. In kidney, ET-1 and ECE1 immunolocalize to vessels and glomeruli, while Ece1/Ece1 mRNA is enriched in endothelial cells; ET-1 can be stored with precursor/ECE1 in Weibel–Palade bodies.	Patel et al., 2024 — https://doi.org/10.1042/bsr20240768; Schiffrin & Pollock, 2024 — https://doi.org/10.1161/hypertensionaha.123.21716; Prepeliuc et al., 2025 — https://doi.org/10.3390/biomedicines13102480	(patel2024comprehensiveanalysisof pages 1-2, patel2024comprehensiveanalysisof media f464fe7a, schiffrin2024endothelinsystemin pages 1-2, prepeliuc2025theinvolvementof pages 4-6)
Key developmental role	In mouse embryos, Edn1 is a crucial pharyngeal arch morphogen. It is produced in arch ectoderm, pharyngeal pouch endoderm, and arch core mesoderm, signals via Ednra on cranial neural crest-derived ectomesenchyme, and is required for mandibular/throat patterning and survival.	Clouthier et al., 2000 — https://doi.org/10.1006/dbio.1999.9527; Tavares et al., 2012 — https://doi.org/10.1016/j.ydbio.2012.08.003; Clouthier et al., 2010 — https://doi.org/10.1002/ajmg.a.33568	(clouthier2000signalingpathwayscrucial pages 1-2, tavares2012ectodermalderivedendothelin1is pages 2-4, tavares2012ectodermalderivedendothelin1is pages 1-2, clouthier2010regulationoffacial pages 16-20)
Kidney/vascular role	ET-1 is a core regulator of vascular tone, blood pressure, and renal physiology/pathophysiology. In the kidney endothelin system, endothelial ECE1 and ET-1 are prominent in glomeruli/endothelium; dysregulated ET-1 contributes to hypertension, CKD, and acute kidney injury models.	Schiffrin & Pollock, 2024 — https://doi.org/10.1161/hypertensionaha.123.21716; Patel et al., 2024 — https://doi.org/10.1042/bsr20240768; Afolabi et al., 2023 — https://doi.org/10.1093/function/zqad022	(schiffrin2024endothelinsystemin pages 1-2, patel2024comprehensiveanalysisof pages 1-2, patel2024comprehensiveanalysisof media f464fe7a)
Translational/clinical relevance	The ET-1/EDN1 pathway remains an active therapeutic target. Recent developments include aprocitentan for resistant hypertension, sparsentan approval in 2023 for IgA nephropathy, genotype-guided ETA-antagonist trials, and biomarker/translational use of ET-axis measurements in portal hypertension and cardiovascular disease.	Abraham et al., 2023 — https://doi.org/10.17863/cam.104737; Owen et al., 2024 — https://doi.org/10.1042/bsr20240528; Schiffrin & Pollock, 2024 — https://doi.org/10.1161/hypertensionaha.123.21716	(abraham2023currentandfuture pages 17-20, abraham2023currentandfuture pages 7-11, owen2024microarrayanalysisdemonstrates pages 1-2, schiffrin2024endothelinsystemin pages 12-14)

Table: This table summarizes the core functional annotation for mouse Edn1/ET-1, including molecular processing, receptors, signaling, localization, developmental roles, and current translational relevance. It is designed to support a concise, evidence-based narrative for UniProt P22387.

8) Visual evidence (kidney localization and single-cell expression)

A 2024 study provides immunolocalization and scRNA-seq visuals supporting kidney localization and expression patterns of endothelin system components, including ET-1 and ECE1 in mouse kidney vessels/glomeruli and dot/violin plots for endothelin system genes across kidney cell clusters. (patel2024comprehensiveanalysisof media f464fe7a, patel2024comprehensiveanalysisof media 735b12ea, patel2024comprehensiveanalysisof media c1e6ece1)

9) Scope notes / limitations

The mechanistic and phenotypic annotation here is strongly supported for mouse Edn1 in craniofacial development (pharyngeal arch patterning) and vascular/kidney biology. Quantitative phenotype penetrance metrics for Edn1 mouse alleles were not directly extractable from the provided excerpts and would require deeper extraction from the original Edn1/Ednra knockout papers.
Some recent translational data pertain to human EDN1 pathway targeting; they are included as “real-world implementations” of the conserved pathway and clearly distinguished from mouse-specific genetic function.

References

(schiffrin2024endothelinsystemin pages 1-2): Ernesto L. Schiffrin and David M. Pollock. Endothelin system in hypertension and chronic kidney disease. Hypertension, 81:691-701, Apr 2024. URL: https://doi.org/10.1161/hypertensionaha.123.21716, doi:10.1161/hypertensionaha.123.21716. This article has 73 citations and is from a domain leading peer-reviewed journal.
(schiffrin2025endothelinantagonistsfor pages 1-2): Ernesto L. Schiffrin. Endothelin antagonists for hypertension: has their time finally arrived? Clinical Science (London, England : 1979), 139:769-776, Jul 2025. URL: https://doi.org/10.1042/cs20255853, doi:10.1042/cs20255853. This article has 2 citations.
(patel2024comprehensiveanalysisof pages 1-2): Margi Patel, Nicholas Harris, Malgorzata Kasztan, and Kelly A. Hyndman. Comprehensive analysis of the endothelin system in the kidneys of mice, rats, and humans. Bioscience Reports, Jul 2024. URL: https://doi.org/10.1042/bsr20240768, doi:10.1042/bsr20240768. This article has 1 citations and is from a peer-reviewed journal.
(clouthier2004understandingendothelin1function pages 1-2): David E. Clouthier and Thomas F. Schilling. Understanding endothelin-1 function during craniofacial development in the mouse and zebrafish. Birth defects research. Part C, Embryo today : reviews, 72 2:190-9, Jun 2004. URL: https://doi.org/10.1002/bdrc.20007, doi:10.1002/bdrc.20007. This article has 70 citations.
(schiffrin2024endothelinsystemin pages 2-4): Ernesto L. Schiffrin and David M. Pollock. Endothelin system in hypertension and chronic kidney disease. Hypertension, 81:691-701, Apr 2024. URL: https://doi.org/10.1161/hypertensionaha.123.21716, doi:10.1161/hypertensionaha.123.21716. This article has 73 citations and is from a domain leading peer-reviewed journal.
(arndt2024endothelinandthe pages 2-2): Philipp F. Arndt, Kati Turkowski, Michael J. Cekay, Bastian Eul, Friedrich Grimminger, and Rajkumar Savai. Endothelin and the tumor microenvironment: a finger in every pie. Clinical Science (London, England : 1979), 138:617-634, May 2024. URL: https://doi.org/10.1042/cs20240426, doi:10.1042/cs20240426. This article has 13 citations.
(prepeliuc2025theinvolvementof pages 4-6): Cristian Sorin Prepeliuc, Maria Antoanela Pasăre, Maria Gabriela Grigoriu, Ionela Larisa Miftode, Radu Ștefan Miftode, Andrei Vâță, Irina Iuliana Costache-Enache, and Egidia Gabriela Miftode. The involvement of endothelin-1 in sepsis and organ dysfunction—a novel biomarker in patient assessment. Biomedicines, 13:2480, Oct 2025. URL: https://doi.org/10.3390/biomedicines13102480, doi:10.3390/biomedicines13102480. This article has 3 citations.
(patel2024comprehensiveanalysisof media f464fe7a): Margi Patel, Nicholas Harris, Malgorzata Kasztan, and Kelly A. Hyndman. Comprehensive analysis of the endothelin system in the kidneys of mice, rats, and humans. Bioscience Reports, Jul 2024. URL: https://doi.org/10.1042/bsr20240768, doi:10.1042/bsr20240768. This article has 1 citations and is from a peer-reviewed journal.
(maiza2026endothelin1inthe pages 1-2): Iman Maiza. Endothelin-1 in the failing fontan: pathobiology, precision therapeutics, and future trial design. Frontiers in Pediatrics, 13:1718057, Feb 2026. URL: https://doi.org/10.3389/fped.2025.1718057, doi:10.3389/fped.2025.1718057. This article has 0 citations.
(clouthier2000signalingpathwayscrucial pages 1-2): David E. Clouthier, S.Clay Williams, Hiromi Yanagisawa, Matthew Wieduwilt, James A. Richardson, and Masashi Yanagisawa. Signaling pathways crucial for craniofacial development revealed by endothelin-a receptor-deficient mice. Developmental biology, 217 1:10-24, Jan 2000. URL: https://doi.org/10.1006/dbio.1999.9527, doi:10.1006/dbio.1999.9527. This article has 241 citations and is from a peer-reviewed journal.
(clouthier2010regulationoffacial pages 6-8): David E. Clouthier, Elvin Garcia, and Thomas F. Schilling. Regulation of facial morphogenesis by endothelin signaling: insights from mice and fish. American Journal of Medical Genetics Part A, 152A:2962-2973, Dec 2010. URL: https://doi.org/10.1002/ajmg.a.33568, doi:10.1002/ajmg.a.33568. This article has 106 citations.
(clouthier2010regulationoffacial pages 2-4): David E. Clouthier, Elvin Garcia, and Thomas F. Schilling. Regulation of facial morphogenesis by endothelin signaling: insights from mice and fish. American Journal of Medical Genetics Part A, 152A:2962-2973, Dec 2010. URL: https://doi.org/10.1002/ajmg.a.33568, doi:10.1002/ajmg.a.33568. This article has 106 citations.
(tavares2012ectodermalderivedendothelin1is pages 1-2): Andre L.P. Tavares, Elvin L. Garcia, Katherine Kuhn, Crystal M. Woods, Trevor Williams, and David E. Clouthier. Ectodermal-derived endothelin1 is required for patterning the distal and intermediate domains of the mouse mandibular arch. Developmental biology, 371 1:47-56, Nov 2012. URL: https://doi.org/10.1016/j.ydbio.2012.08.003, doi:10.1016/j.ydbio.2012.08.003. This article has 44 citations and is from a peer-reviewed journal.
(tavares2012ectodermalderivedendothelin1is pages 2-4): Andre L.P. Tavares, Elvin L. Garcia, Katherine Kuhn, Crystal M. Woods, Trevor Williams, and David E. Clouthier. Ectodermal-derived endothelin1 is required for patterning the distal and intermediate domains of the mouse mandibular arch. Developmental biology, 371 1:47-56, Nov 2012. URL: https://doi.org/10.1016/j.ydbio.2012.08.003, doi:10.1016/j.ydbio.2012.08.003. This article has 44 citations and is from a peer-reviewed journal.
(abraham2023currentandfuture pages 1-4): George R. Abraham, Thomas L. Williams, J. Maguire, Peter J. Greasley, Philip Ambery, and A. Davenport. Current and future strategies for targeting the endothelin pathway in cardiovascular disease. JournalArticle, Dec 2023. URL: https://doi.org/10.17863/cam.104737, doi:10.17863/cam.104737. This article has 25 citations.
(abraham2023currentandfuture pages 7-11): George R. Abraham, Thomas L. Williams, J. Maguire, Peter J. Greasley, Philip Ambery, and A. Davenport. Current and future strategies for targeting the endothelin pathway in cardiovascular disease. JournalArticle, Dec 2023. URL: https://doi.org/10.17863/cam.104737, doi:10.17863/cam.104737. This article has 25 citations.
(abraham2023currentandfuture pages 17-20): George R. Abraham, Thomas L. Williams, J. Maguire, Peter J. Greasley, Philip Ambery, and A. Davenport. Current and future strategies for targeting the endothelin pathway in cardiovascular disease. JournalArticle, Dec 2023. URL: https://doi.org/10.17863/cam.104737, doi:10.17863/cam.104737. This article has 25 citations.
(owen2024microarrayanalysisdemonstrates pages 1-2): Nicola E. Owen, Thomas L. Williams, Janet J. Maguire, Rhoda E. Kuc, Emma E. Davenport, and Anthony P. Davenport. Microarray analysis demonstrates up-regulation of the endothelin-1 gene with compensatory down-regulation of the eta receptor gene in human portal vein. Bioscience Reports, Jul 2024. URL: https://doi.org/10.1042/bsr20240528, doi:10.1042/bsr20240528. This article has 5 citations and is from a peer-reviewed journal.
(clouthier2010regulationoffacial pages 16-20): David E. Clouthier, Elvin Garcia, and Thomas F. Schilling. Regulation of facial morphogenesis by endothelin signaling: insights from mice and fish. American Journal of Medical Genetics Part A, 152A:2962-2973, Dec 2010. URL: https://doi.org/10.1002/ajmg.a.33568, doi:10.1002/ajmg.a.33568. This article has 106 citations.
(schiffrin2024endothelinsystemin pages 12-14): Ernesto L. Schiffrin and David M. Pollock. Endothelin system in hypertension and chronic kidney disease. Hypertension, 81:691-701, Apr 2024. URL: https://doi.org/10.1161/hypertensionaha.123.21716, doi:10.1161/hypertensionaha.123.21716. This article has 73 citations and is from a domain leading peer-reviewed journal.
(patel2024comprehensiveanalysisof media 735b12ea): Margi Patel, Nicholas Harris, Malgorzata Kasztan, and Kelly A. Hyndman. Comprehensive analysis of the endothelin system in the kidneys of mice, rats, and humans. Bioscience Reports, Jul 2024. URL: https://doi.org/10.1042/bsr20240768, doi:10.1042/bsr20240768. This article has 1 citations and is from a peer-reviewed journal.
(patel2024comprehensiveanalysisof media c1e6ece1): Margi Patel, Nicholas Harris, Malgorzata Kasztan, and Kelly A. Hyndman. Comprehensive analysis of the endothelin system in the kidneys of mice, rats, and humans. Bioscience Reports, Jul 2024. URL: https://doi.org/10.1042/bsr20240768, doi:10.1042/bsr20240768. This article has 1 citations and is from a peer-reviewed journal.

Citations

prepeliuc2025theinvolvementof pages 4-6
abraham2023currentandfuture pages 17-20
abraham2023currentandfuture pages 1-4
owen2024microarrayanalysisdemonstrates pages 1-2
abraham2023currentandfuture pages 7-11
patel2024comprehensiveanalysisof pages 1-2
schiffrin2024endothelinsystemin pages 1-2
schiffrin2025endothelinantagonistsfor pages 1-2
schiffrin2024endothelinsystemin pages 2-4
arndt2024endothelinandthe pages 2-2
clouthier2000signalingpathwayscrucial pages 1-2
clouthier2010regulationoffacial pages 6-8
clouthier2010regulationoffacial pages 2-4
clouthier2010regulationoffacial pages 16-20
schiffrin2024endothelinsystemin pages 12-14
https://doi.org/10.1161/hypertensionaha.123.21716;
https://doi.org/10.1042/bsr20240768
https://doi.org/10.1042/cs20255853
https://doi.org/10.1042/cs20240426;
https://doi.org/10.3390/biomedicines13102480
https://doi.org/10.3390/biomedicines13102480;
https://doi.org/10.3389/fped.2025.1718057
https://doi.org/10.1042/bsr20240768;
https://doi.org/10.1006/dbio.1999.9527;
https://doi.org/10.1016/j.ydbio.2012.08.003;
https://doi.org/10.1002/ajmg.a.33568
https://doi.org/10.1093/function/zqad022
https://doi.org/10.17863/cam.104737;
https://doi.org/10.1042/bsr20240528;
https://doi.org/10.1161/hypertensionaha.123.21716
https://doi.org/10.1161/hypertensionaha.123.21716,
https://doi.org/10.1042/cs20255853,
https://doi.org/10.1042/bsr20240768,
https://doi.org/10.1002/bdrc.20007,
https://doi.org/10.1042/cs20240426,
https://doi.org/10.3390/biomedicines13102480,
https://doi.org/10.3389/fped.2025.1718057,
https://doi.org/10.1006/dbio.1999.9527,
https://doi.org/10.1002/ajmg.a.33568,
https://doi.org/10.1016/j.ydbio.2012.08.003,
https://doi.org/10.17863/cam.104737,
https://doi.org/10.1042/bsr20240528,

Notes

(Edn1-notes.md)

Edn1 curation notes

Evidence synthesis

Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. UniProt summarizes endothelins as "endothelium-derived vasoconstrictor peptides" and describes ET-1 as a "Probable ligand for G-protein coupled receptors EDNRA and EDNRB." [file:mouse/Edn1/Edn1-uniprot.txt]
Core receptor binding and signaling: Endothelin stimulates high-affinity receptor binding and phospholipase C signaling in fibroblasts; the abstract reports that endothelin "specifically binds to a single class of high affinity receptors" and "stimulates phospholipase C with the production of second messengers inositol trisphosphate and 1,2-diacylglycerol." [PMID:2542249 "A novel vasoactive peptide endothelin stimulates mitogenesis through inositol lipid turnover in Swiss 3T3 fibroblasts.", "specifically binds to a single class of high affinity receptors ... stimulates phospholipase C"]
Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure." This supports Edn1 as a physiological regulator of vascular tone and blood pressure, while broad organismal phenotypes remain non-core relative to ligand activity. [PMID:8152482 "Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1.", "ET-1+/- heterozygous mice, which produce lower levels of ET-1 than wild-type mice, develop elevated blood pressure"]
Cardiovascular development: Edn1-/- mice have "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract." These defects support developmental annotations for heart and great-vessel morphogenesis, but they are best treated as non-core developmental consequences of endothelin receptor signaling. [PMID:7615798 "Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1.", "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract"]
Neural crest patterning: Edn1/Ednra signaling is required for branchial arch patterning; one paper states that Edn1 "regulates the dorsoventral branchial arch patterning in mice." These annotations are supported when specific to cranial/cardiac neural crest patterning but should not be generalized to all development. PMID:15110048
Sympathetic axon guidance: Venous endothelin-1 is a direct guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin controls growth and guidance of the STG axons to the heart." Poltavski et al. report that "endothelin-1 induces sympathetic neurons expressing the receptor Ednra to project to the vena cavae leading to the heart." These support cardiac sympathetic axon-guidance annotations as well-supported but non-core developmental signaling roles. [PMID:24875861 "Venous endothelin guides sympathetic innervation of the developing mouse heart.", "vascular-derived endothelin controls growth and guidance of the STG axons to the heart"] [PMID:30735130 "Venous endothelin modulates responsiveness of cardiac sympathetic axons to arterial semaphorin.", "endothelin-1 induces sympathetic neurons expressing the receptor Ednra to project to the vena cavae leading to the heart"]
Kidney and podocyte disease evidence: Endothelin-1 stimulation of primary mouse podocytes "elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)" and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models. These support renal/podocyte annotations when direct, but disease-model terms are not core Edn1 function. [PMID:24722437 "Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis.", "elicited rapid calcium transients mediated by endothelin type A receptors"] PMID:31402170
Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation. Prefer the more specific ligand/receptor-binding and endothelin receptor signaling terms; keep direct mouse developmental or renal phenotypes as non-core rather than core functions.
Falcon integration: the Falcon report independently supports the same core model: Edn1 encodes the preproendothelin-1 precursor processed to mature ET-1, a secreted peptide hormone/vasoconstrictor that signals through ETA/EDNRA and ETB/EDNRB receptors. It also emphasizes extracellular ligand localization, endothelial/glomerular production, vascular tone, renal physiology, and pharyngeal-arch morphogen activity; this reinforced ACCEPT for hormone/endothelin receptor binding and endothelin receptor signaling terms, while keeping broad downstream or phenotype terms non-core or over-annotated. [file:mouse/Edn1/Edn1-deep-research-falcon.md "encodes a secreted peptide hormone precursor"; "signals primarily via two class A GPCRs"]

📄 View Raw YAML

id: P22387
gene_symbol: Edn1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:10090
  label: Mus musculus
description: 'Edn1 encodes preproendothelin-1, the precursor of the secreted endothelin-1
  peptide. Mature ET-1 binds endothelin A and B receptors to regulate vascular smooth
  muscle contraction, blood pressure, renal/podocyte signaling, craniofacial and cardiovascular
  development, and sympathetic axon guidance.'
existing_annotations:
- term:
    id: GO:0006874
    label: intracellular calcium ion homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: intracellular calcium ion homeostasis is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Kidney and podocyte disease evidence: Endothelin-1 stimulation
        of primary mouse podocytes "elicited rapid calcium transients mediated by
        endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)"
        and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.'
- term:
    id: GO:0045987
    label: positive regulation of smooth muscle contraction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: positive regulation of smooth muscle contraction is biologically
      consistent with the curated synthesis for Edn1 and is supported by IBA
      evidence (GO_REF:0000033).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon identifies ET-1 as a potent vasoconstrictor whose
        ETA signaling in vascular smooth muscle promotes sustained contraction.
- term:
    id: GO:0003100
    label: regulation of systemic arterial blood pressure by endothelin
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: regulation of systemic arterial blood pressure by endothelin is
      biologically consistent with the curated synthesis for Edn1 and is
      supported by IBA evidence (GO_REF:0000033).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon summarizes ET-1 as a central regulator of vascular
        tone and blood pressure through receptor-specific endothelin signaling.
- term:
    id: GO:0005179
    label: hormone activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: hormone activity is biologically consistent with the curated
      synthesis for Edn1 and is supported by IBA evidence (GO_REF:0000033).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon describes Edn1 as encoding a secreted peptide
        hormone precursor that yields mature endothelin-1, supporting
        hormone/receptor ligand activity.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: extracellular space is biologically consistent with the curated
      synthesis for Edn1 and is supported by IBA evidence (GO_REF:0000033).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon states that ET-1 functions as an extracellular
        ligand produced by endothelial and epithelial cells.
- term:
    id: GO:0014826
    label: vein smooth muscle contraction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: vein smooth muscle contraction is biologically consistent with the
      curated synthesis for Edn1 and is supported by IBA evidence
      (GO_REF:0000033).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0031707
    label: endothelin A receptor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: endothelin A receptor binding is biologically consistent with the
      curated synthesis for Edn1 and is supported by IBA evidence
      (GO_REF:0000033).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon reports that mature ET-1 signals through ETA/EDNRA
        receptors, supporting endothelin A receptor binding.
- term:
    id: GO:0031708
    label: endothelin B receptor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: endothelin B receptor binding is biologically consistent with the
      curated synthesis for Edn1 and is supported by IBA evidence
      (GO_REF:0000033).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon reports that mature ET-1 signals through ETB/EDNRB
        receptors, supporting endothelin B receptor binding.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: extracellular region is biologically consistent with the curated
      synthesis for Edn1 and is supported by IEA evidence (GO_REF:0000120).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon states that ET-1 functions as an extracellular
        ligand produced by endothelial and epithelial cells.
- term:
    id: GO:0019229
    label: regulation of vasoconstriction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: regulation of vasoconstriction captures the right general biology
      for Edn1, but a more specific GO term is available.
    action: MODIFY
    reason: The current term is too broad or less precise than vasoconstriction
      for this gene. Replace with vasoconstriction to align the annotation with
      the reviewed evidence.
    proposed_replacement_terms:
    - id: GO:0042310
      label: vasoconstriction
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0042310
    label: vasoconstriction
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: vasoconstriction is biologically consistent with the curated
      synthesis for Edn1 and is supported by IEA evidence (GO_REF:0000120).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0097746
    label: blood vessel diameter maintenance
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: blood vessel diameter maintenance is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: negative regulation of transcription by RNA polymerase II is
      related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: response to hypoxia is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0001821
    label: histamine secretion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: histamine secretion is related to reported Edn1 biology only as a
      broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0003100
    label: regulation of systemic arterial blood pressure by endothelin
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: regulation of systemic arterial blood pressure by endothelin is
      biologically consistent with the curated synthesis for Edn1 and is
      supported by IEA evidence (GO_REF:0000107).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon summarizes ET-1 as a central regulator of vascular
        tone and blood pressure through receptor-specific endothelin signaling.
- term:
    id: GO:0005125
    label: cytokine activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cytokine activity captures the right general biology for Edn1, but
      a more specific GO term is available.
    action: MODIFY
    reason: The current term is too broad or less precise than receptor ligand
      activity for this gene. Replace with receptor ligand activity to align the
      annotation with the reviewed evidence.
    proposed_replacement_terms:
    - id: GO:0048018
      label: receptor ligand activity
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
- term:
    id: GO:0005179
    label: hormone activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: hormone activity is biologically consistent with the curated
      synthesis for Edn1 and is supported by IEA evidence (GO_REF:0000107).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon describes Edn1 as encoding a secreted peptide
        hormone precursor that yields mature endothelin-1, supporting
        hormone/receptor ligand activity.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: extracellular space is biologically consistent with the curated
      synthesis for Edn1 and is supported by IEA evidence (GO_REF:0000120).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon states that ET-1 functions as an extracellular
        ligand produced by endothelial and epithelial cells.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cytoplasm is not supported as an appropriate annotation for Edn1
      after review of the available mouse evidence.
    action: REMOVE
    reason: The term appears to reflect either an unsupported transfer, a
      paralog/family overreach, or a localization/process inconsistent with the
      curated Edn1 biology.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0006874
    label: intracellular calcium ion homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: intracellular calcium ion homeostasis is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Kidney and podocyte disease evidence: Endothelin-1 stimulation
        of primary mouse podocytes "elicited rapid calcium transients mediated by
        endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)"
        and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.'
- term:
    id: GO:0007166
    label: cell surface receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cell surface receptor signaling pathway captures the right general
      biology for Edn1, but a more specific GO term is available.
    action: MODIFY
    reason: The current term is too broad or less precise than endothelin
      receptor signaling pathway for this gene. Replace with endothelin receptor
      signaling pathway to align the annotation with the reviewed evidence.
    proposed_replacement_terms:
    - id: GO:0086100
      label: endothelin receptor signaling pathway
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: G protein-coupled receptor signaling pathway captures the right
      general biology for Edn1, but a more specific GO term is available.
    action: MODIFY
    reason: The current term is too broad or less precise than endothelin
      receptor signaling pathway for this gene. Replace with endothelin receptor
      signaling pathway to align the annotation with the reviewed evidence.
    proposed_replacement_terms:
    - id: GO:0086100
      label: endothelin receptor signaling pathway
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0007204
    label: positive regulation of cytosolic calcium ion concentration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of cytosolic calcium ion concentration is
      related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0007267
    label: cell-cell signaling
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cell-cell signaling is biologically consistent with secreted paracrine Edn1 ligand activity but is less specific than endothelin receptor signaling.
    action: KEEP_AS_NON_CORE
    reason: Edn1 is a secreted peptide ligand that mediates receptor-dependent communication between cells; retain the broad signaling term as non-core while preferring endothelin receptor signaling and receptor ligand terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1,
        processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin
        receptors EDNRA and EDNRB.'
- term:
    id: GO:0008217
    label: regulation of blood pressure
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: regulation of blood pressure is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: positive regulation of cell population proliferation is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0009410
    label: response to xenobiotic stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: response to xenobiotic stimulus is related to reported Edn1 biology
      only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0010193
    label: response to ozone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: response to ozone is related to reported Edn1 biology only as a
      broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0010460
    label: positive regulation of heart rate
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of heart rate is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: PMID:23933587
      supporting_text: Edn1 and Ednra knock-out mice demonstrate abnormalities
        in pharyngeal arch artery patterning
- term:
    id: GO:0010613
    label: positive regulation of cardiac muscle hypertrophy
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of cardiac muscle hypertrophy is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: negative regulation of gene expression is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0014823
    label: response to activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: response to activity is related to reported Edn1 biology only as a
      broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0014824
    label: artery smooth muscle contraction
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: artery smooth muscle contraction is a direct vascular output of
      endothelin-1 receptor signaling.
    action: ACCEPT
    reason: ET-1 is a vasoactive peptide ligand whose ETA/EDNRA signaling in
      vascular smooth muscle drives vasoconstriction through PLC/calcium signaling,
      making this term consistent with the curated vascular contraction function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: 'ETA (EDNRA/ETAR): classically enriched on vascular smooth
        muscle cells (VSMCs) and mediates potent, sustained vasoconstriction and
        growth/remodeling programs.'
- term:
    id: GO:0014826
    label: vein smooth muscle contraction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: vein smooth muscle contraction is biologically consistent with the
      curated synthesis for Edn1 and is supported by IEA evidence
      (GO_REF:0000107).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0019722
    label: calcium-mediated signaling
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: calcium-mediated signaling is related to reported Edn1 biology only
      as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0023019
    label: signal transduction involved in regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: signal transduction involved in regulation of gene expression is
      related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0030072
    label: peptide hormone secretion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: peptide hormone secretion is related to reported Edn1 biology only
      as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0030185
    label: nitric oxide transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: nitric oxide transport is related to reported Edn1 biology only as
      a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of cell migration is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0031707
    label: endothelin A receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: endothelin A receptor binding is biologically consistent with the
      curated synthesis for Edn1 and is supported by IEA evidence
      (GO_REF:0000120).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon reports that mature ET-1 signals through ETA/EDNRA
        receptors, supporting endothelin A receptor binding.
- term:
    id: GO:0031708
    label: endothelin B receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: endothelin B receptor binding is biologically consistent with the
      curated synthesis for Edn1 and is supported by IEA evidence
      (GO_REF:0000120).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon reports that mature ET-1 signals through ETB/EDNRB
        receptors, supporting endothelin B receptor binding.
- term:
    id: GO:0032308
    label: positive regulation of prostaglandin secretion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of prostaglandin secretion is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0032496
    label: response to lipopolysaccharide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: response to lipopolysaccharide is related to reported Edn1 biology
      only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0033093
    label: Weibel-Palade body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Weibel-Palade body localization reflects endothelial regulated
      storage/secretion of ET-1 precursor-processing components.
    action: KEEP_AS_NON_CORE
    reason: This supports regulated endothelial storage and secretion of ET-1,
      but remains a localization/trafficking context rather than the core ligand
      signaling role.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: ET-1 precursors and processing components can be stored in
        endothelial secretory vesicles, particularly Weibel-Palade bodies, with
        reported co-localization of pro-ET-1 and ECE-1.
- term:
    id: GO:0033574
    label: response to testosterone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: response to testosterone is related to reported Edn1 biology only
      as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0034392
    label: negative regulation of smooth muscle cell apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: negative regulation of smooth muscle cell apoptotic process is
      related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0034696
    label: response to prostaglandin F
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: response to prostaglandin F is related to reported Edn1 biology
      only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0035094
    label: response to nicotine
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: response to nicotine is related to reported Edn1 biology only as a
      broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: intracellular signal transduction is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0035994
    label: response to muscle stretch
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: response to muscle stretch is related to reported Edn1 biology only
      as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0042045
    label: epithelial fluid transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: epithelial fluid transport is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0042482
    label: positive regulation of odontogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of odontogenesis is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0042554
    label: superoxide anion generation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: superoxide anion generation is related to reported Edn1 biology
      only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0043200
    label: response to amino acid
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: response to amino acid is related to reported Edn1 biology only as
      a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0043410
    label: positive regulation of MAPK cascade
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of MAPK cascade is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0043491
    label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: phosphatidylinositol 3-kinase/protein kinase B signal transduction
      is related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0044321
    label: response to leptin
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: response to leptin is related to reported Edn1 biology only as a
      broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0045178
    label: basal part of cell
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: The local evidence supports Edn1 as a secreted ligand but does not
      verify this specific basal-cell localization.
    action: UNDECIDED
    reason: The generic secreted-ligand evidence and Weibel-Palade storage model
      do not establish a basal part of cell annotation for Edn1.
- term:
    id: GO:0045793
    label: positive regulation of cell size
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of cell size is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0045840
    label: positive regulation of mitotic nuclear division
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of mitotic nuclear division is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: positive regulation of transcription by RNA polymerase II is
      related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0045987
    label: positive regulation of smooth muscle contraction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of smooth muscle contraction is biologically
      consistent with the curated synthesis for Edn1 and is supported by IEA
      evidence (GO_REF:0000107).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon identifies ET-1 as a potent vasoconstrictor whose
        ETA signaling in vascular smooth muscle promotes sustained contraction.
- term:
    id: GO:0046330
    label: positive regulation of JNK cascade
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of JNK cascade is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0046887
    label: positive regulation of hormone secretion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of hormone secretion is related to reported
      Edn1 biology only as a broad downstream readout or generic interaction
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0046888
    label: negative regulation of hormone secretion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: negative regulation of hormone secretion is related to reported
      Edn1 biology only as a broad downstream readout or generic interaction
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0048237
    label: rough endoplasmic reticulum lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: The local evidence supports Edn1 as a secreted peptide precursor,
      but does not verify a rough endoplasmic reticulum lumen localization.
    action: UNDECIDED
    reason: Secretory-protein biology alone is not enough to retain this specific
      automated cellular-component annotation without direct localization evidence.
- term:
    id: GO:0048661
    label: positive regulation of smooth muscle cell proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of smooth muscle cell proliferation is related
      to reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0050850
    label: positive regulation of calcium-mediated signaling
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of calcium-mediated signaling is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0051248
    label: negative regulation of protein metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: negative regulation of protein metabolic process is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0051899
    label: membrane depolarization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: membrane depolarization is related to reported Edn1 biology only as
      a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0060137
    label: maternal process involved in parturition
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: maternal process involved in parturition is related to reported
      Edn1 biology only as a broad downstream readout or generic interaction
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0060298
    label: positive regulation of sarcomere organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of sarcomere organization is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0061051
    label: positive regulation of cell growth involved in cardiac muscle cell
      development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of cell growth involved in cardiac muscle cell
      development is related to reported Edn1 biology only as a broad downstream
      readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: PMID:23933587
      supporting_text: Edn1/Ednra signaling is involved in pharyngeal artery
        development by controlling the fate of neural crest cells
- term:
    id: GO:0070301
    label: cellular response to hydrogen peroxide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cellular response to hydrogen peroxide is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0071277
    label: cellular response to calcium ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cellular response to calcium ion is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0071346
    label: cellular response to type II interferon
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cellular response to type II interferon is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0071347
    label: cellular response to interleukin-1
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cellular response to interleukin-1 is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0071356
    label: cellular response to tumor necrosis factor
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cellular response to tumor necrosis factor is related to reported
      Edn1 biology only as a broad downstream readout or generic interaction
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0071375
    label: cellular response to peptide hormone stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cellular response to peptide hormone stimulus is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0071385
    label: cellular response to glucocorticoid stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cellular response to glucocorticoid stimulus is related to reported
      Edn1 biology only as a broad downstream readout or generic interaction
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0071389
    label: cellular response to mineralocorticoid stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cellular response to mineralocorticoid stimulus is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0071398
    label: cellular response to fatty acid
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cellular response to fatty acid is related to reported Edn1 biology
      only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0071456
    label: cellular response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cellular response to hypoxia is related to reported Edn1 biology
      only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0071466
    label: cellular response to xenobiotic stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cellular response to xenobiotic stimulus is related to reported
      Edn1 biology only as a broad downstream readout or generic interaction
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0071548
    label: response to dexamethasone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: response to dexamethasone is related to reported Edn1 biology only
      as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0071559
    label: response to transforming growth factor beta
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: response to transforming growth factor beta is related to reported
      Edn1 biology only as a broad downstream readout or generic interaction
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0071560
    label: cellular response to transforming growth factor beta stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cellular response to transforming growth factor beta stimulus is
      related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0086100
    label: endothelin receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: endothelin receptor signaling pathway is biologically consistent
      with the curated synthesis for Edn1 and is supported by IEA evidence
      (GO_REF:0000107).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core receptor binding and signaling: Endothelin stimulates
        high-affinity receptor binding and phospholipase C signaling in fibroblasts;
        the abstract reports that endothelin "specifically binds to a single class
        of high affinity receptors" and "stimulates phospholipase C with the production
        of second messengers inositol trisphosphate and 1,2-diacylglycerol."'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: 'Falcon summarizes the canonical endothelin receptor pathway:
        ET-1 activates ETA/ETB GPCRs with Gq/11-PLC-calcium/PKC and other downstream
        signaling.'
- term:
    id: GO:0090023
    label: positive regulation of neutrophil chemotaxis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of neutrophil chemotaxis is related to reported
      Edn1 biology only as a broad downstream readout or generic interaction
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0097237
    label: cellular response to toxic substance
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cellular response to toxic substance is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0141156
    label: cAMP/PKA signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cAMP/PKA signal transduction is related to reported Edn1 biology
      only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0160195
    label: negative regulation of phospholipase C/protein kinase C signal
      transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: negative regulation of phospholipase C/protein kinase C signal
      transduction is related to reported Edn1 biology only as a broad
      downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:1901224
    label: positive regulation of non-canonical NF-kappaB signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of non-canonical NF-kappaB signal transduction
      is related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:1902074
    label: response to salt
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: response to salt is related to reported Edn1 biology only as a
      broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:1904707
    label: positive regulation of vascular associated smooth muscle cell
      proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of vascular associated smooth muscle cell
      proliferation is related to reported Edn1 biology only as a broad
      downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: negative regulation of transcription by RNA polymerase II is
      related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0003100
    label: regulation of systemic arterial blood pressure by endothelin
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: regulation of systemic arterial blood pressure by endothelin is
      biologically consistent with the curated synthesis for Edn1 and is
      supported by ISO evidence (GO_REF:0000119).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon summarizes ET-1 as a central regulator of vascular
        tone and blood pressure through receptor-specific endothelin signaling.
- term:
    id: GO:0005125
    label: cytokine activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: cytokine activity captures the right general biology for Edn1, but
      a more specific GO term is available.
    action: MODIFY
    reason: The current term is too broad or less precise than receptor ligand
      activity for this gene. Replace with receptor ligand activity to align the
      annotation with the reviewed evidence.
    proposed_replacement_terms:
    - id: GO:0048018
      label: receptor ligand activity
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
- term:
    id: GO:0005179
    label: hormone activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: hormone activity is biologically consistent with the curated
      synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000119).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon describes Edn1 as encoding a secreted peptide
        hormone precursor that yields mature endothelin-1, supporting
        hormone/receptor ligand activity.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: extracellular space is biologically consistent with the curated
      synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000119).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon states that ET-1 functions as an extracellular
        ligand produced by endothelial and epithelial cells.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: cytoplasm is not supported as an appropriate annotation for Edn1
      after review of the available mouse evidence.
    action: REMOVE
    reason: The term appears to reflect either an unsupported transfer, a
      paralog/family overreach, or a localization/process inconsistent with the
      curated Edn1 biology.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0007166
    label: cell surface receptor signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: cell surface receptor signaling pathway captures the right general
      biology for Edn1, but a more specific GO term is available.
    action: MODIFY
    reason: The current term is too broad or less precise than endothelin
      receptor signaling pathway for this gene. Replace with endothelin receptor
      signaling pathway to align the annotation with the reviewed evidence.
    proposed_replacement_terms:
    - id: GO:0086100
      label: endothelin receptor signaling pathway
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: G protein-coupled receptor signaling pathway captures the right
      general biology for Edn1, but a more specific GO term is available.
    action: MODIFY
    reason: The current term is too broad or less precise than endothelin
      receptor signaling pathway for this gene. Replace with endothelin receptor
      signaling pathway to align the annotation with the reviewed evidence.
    proposed_replacement_terms:
    - id: GO:0086100
      label: endothelin receptor signaling pathway
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0007267
    label: cell-cell signaling
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: cell-cell signaling is biologically consistent with secreted paracrine Edn1 ligand activity but is less specific than endothelin receptor signaling.
    action: KEEP_AS_NON_CORE
    reason: Edn1 is a secreted peptide ligand that mediates receptor-dependent communication between cells; retain the broad signaling term as non-core while preferring endothelin receptor signaling and receptor ligand terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1,
        processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin
        receptors EDNRA and EDNRB.'
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of cell population proliferation is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0010460
    label: positive regulation of heart rate
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of heart rate is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: PMID:23933587
      supporting_text: controlling the fate of neural crest cells through a
        Dlx5/Dlx6-independent mechanism
- term:
    id: GO:0010613
    label: positive regulation of cardiac muscle hypertrophy
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of cardiac muscle hypertrophy is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: negative regulation of gene expression is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0014824
    label: artery smooth muscle contraction
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: artery smooth muscle contraction is a direct vascular output of
      endothelin-1 receptor signaling.
    action: ACCEPT
    reason: ET-1 is a vasoactive peptide ligand whose ETA/EDNRA signaling in
      vascular smooth muscle drives vasoconstriction through PLC/calcium signaling,
      making this term consistent with the curated vascular contraction function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: 'ETA (EDNRA/ETAR): classically enriched on vascular smooth
        muscle cells (VSMCs) and mediates potent, sustained vasoconstriction and
        growth/remodeling programs.'
- term:
    id: GO:0014826
    label: vein smooth muscle contraction
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: vein smooth muscle contraction is biologically consistent with the
      curated synthesis for Edn1 and is supported by ISO evidence
      (GO_REF:0000119).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0019722
    label: calcium-mediated signaling
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: calcium-mediated signaling is related to reported Edn1 biology only
      as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0023019
    label: signal transduction involved in regulation of gene expression
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: signal transduction involved in regulation of gene expression is
      related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0030072
    label: peptide hormone secretion
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: peptide hormone secretion is related to reported Edn1 biology only
      as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0030185
    label: nitric oxide transport
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: nitric oxide transport is related to reported Edn1 biology only as
      a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of cell migration is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0031394
    label: positive regulation of prostaglandin biosynthetic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of prostaglandin biosynthetic process is
      supported for Edn1 in a tissue, developmental, trafficking, or
      disease-model context, but it is not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0031707
    label: endothelin A receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: endothelin A receptor binding is biologically consistent with the
      curated synthesis for Edn1 and is supported by ISO evidence
      (GO_REF:0000119).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon reports that mature ET-1 signals through ETA/EDNRA
        receptors, supporting endothelin A receptor binding.
- term:
    id: GO:0031708
    label: endothelin B receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: endothelin B receptor binding is biologically consistent with the
      curated synthesis for Edn1 and is supported by ISO evidence
      (GO_REF:0000119).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon reports that mature ET-1 signals through ETB/EDNRB
        receptors, supporting endothelin B receptor binding.
- term:
    id: GO:0042310
    label: vasoconstriction
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: vasoconstriction is biologically consistent with the curated
      synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000119).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0043410
    label: positive regulation of MAPK cascade
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of MAPK cascade is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0043491
    label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: phosphatidylinositol 3-kinase/protein kinase B signal transduction
      is related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0045793
    label: positive regulation of cell size
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of cell size is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0045840
    label: positive regulation of mitotic nuclear division
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of mitotic nuclear division is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of transcription by RNA polymerase II is
      related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0046330
    label: positive regulation of JNK cascade
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of JNK cascade is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0046887
    label: positive regulation of hormone secretion
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of hormone secretion is related to reported
      Edn1 biology only as a broad downstream readout or generic interaction
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0048661
    label: positive regulation of smooth muscle cell proliferation
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of smooth muscle cell proliferation is related
      to reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0050850
    label: positive regulation of calcium-mediated signaling
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of calcium-mediated signaling is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0051248
    label: negative regulation of protein metabolic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: negative regulation of protein metabolic process is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0060298
    label: positive regulation of sarcomere organization
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of sarcomere organization is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0061051
    label: positive regulation of cell growth involved in cardiac muscle cell
      development
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of cell growth involved in cardiac muscle cell
      development is related to reported Edn1 biology only as a broad downstream
      readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: PMID:15110048
      supporting_text: ET-1/EdnrA signaling may contribute to the dorsoventral
        axis patterning of the branchial arch system
- term:
    id: GO:0070101
    label: positive regulation of chemokine-mediated signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: positive regulation of chemokine-mediated signaling pathway is
      related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0086100
    label: endothelin receptor signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: endothelin receptor signaling pathway is biologically consistent
      with the curated synthesis for Edn1 and is supported by ISO evidence
      (GO_REF:0000119).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core receptor binding and signaling: Endothelin stimulates
        high-affinity receptor binding and phospholipase C signaling in fibroblasts;
        the abstract reports that endothelin "specifically binds to a single class
        of high affinity receptors" and "stimulates phospholipase C with the production
        of second messengers inositol trisphosphate and 1,2-diacylglycerol."'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: 'Falcon summarizes the canonical endothelin receptor pathway:
        ET-1 activates ETA/ETB GPCRs with Gq/11-PLC-calcium/PKC and other downstream
        signaling.'
- term:
    id: GO:0160195
    label: negative regulation of phospholipase C/protein kinase C signal
      transduction
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: negative regulation of phospholipase C/protein kinase C signal
      transduction is related to reported Edn1 biology only as a broad
      downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0001821
    label: histamine secretion
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: histamine secretion is related to reported Edn1 biology only as a
      broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: extracellular space is biologically consistent with the curated
      synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000096).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon states that ET-1 functions as an extracellular
        ligand produced by endothelial and epithelial cells.
- term:
    id: GO:0007204
    label: positive regulation of cytosolic calcium ion concentration
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: positive regulation of cytosolic calcium ion concentration is
      related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0008217
    label: regulation of blood pressure
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: regulation of blood pressure is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: positive regulation of cell population proliferation is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: negative regulation of gene expression is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0014824
    label: artery smooth muscle contraction
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: artery smooth muscle contraction is a direct vascular output of
      endothelin-1 receptor signaling.
    action: ACCEPT
    reason: ET-1 is a vasoactive peptide ligand whose ETA/EDNRA signaling in
      vascular smooth muscle drives vasoconstriction through PLC/calcium signaling,
      making this term consistent with the curated vascular contraction function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: 'ETA (EDNRA/ETAR): classically enriched on vascular smooth
        muscle cells (VSMCs) and mediates potent, sustained vasoconstriction and
        growth/remodeling programs.'
- term:
    id: GO:0031707
    label: endothelin A receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: endothelin A receptor binding is biologically consistent with the
      curated synthesis for Edn1 and is supported by ISO evidence
      (GO_REF:0000096).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon reports that mature ET-1 signals through ETA/EDNRA
        receptors, supporting endothelin A receptor binding.
- term:
    id: GO:0031708
    label: endothelin B receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: endothelin B receptor binding is biologically consistent with the
      curated synthesis for Edn1 and is supported by ISO evidence
      (GO_REF:0000096).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon reports that mature ET-1 signals through ETB/EDNRB
        receptors, supporting endothelin B receptor binding.
- term:
    id: GO:0032308
    label: positive regulation of prostaglandin secretion
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: positive regulation of prostaglandin secretion is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0033093
    label: Weibel-Palade body
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Weibel-Palade body localization reflects endothelial regulated
      storage/secretion of ET-1 precursor-processing components.
    action: KEEP_AS_NON_CORE
    reason: This supports regulated endothelial storage and secretion of ET-1,
      but remains a localization/trafficking context rather than the core ligand
      signaling role.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: ET-1 precursors and processing components can be stored in
        endothelial secretory vesicles, particularly Weibel-Palade bodies, with
        reported co-localization of pro-ET-1 and ECE-1.
- term:
    id: GO:0034392
    label: negative regulation of smooth muscle cell apoptotic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: negative regulation of smooth muscle cell apoptotic process is
      related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: intracellular signal transduction is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0042045
    label: epithelial fluid transport
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: epithelial fluid transport is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0042310
    label: vasoconstriction
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: vasoconstriction is biologically consistent with the curated
      synthesis for Edn1 and is supported by ISO evidence (GO_REF:0000096).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0042482
    label: positive regulation of odontogenesis
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: positive regulation of odontogenesis is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0042554
    label: superoxide anion generation
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: superoxide anion generation is related to reported Edn1 biology
      only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0045178
    label: basal part of cell
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: The local evidence supports Edn1 as a secreted ligand but does not
      verify this specific basal-cell localization.
    action: UNDECIDED
    reason: The generic secreted-ligand evidence and Weibel-Palade storage model
      do not establish a basal part of cell annotation for Edn1.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: positive regulation of transcription by RNA polymerase II is
      related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0045987
    label: positive regulation of smooth muscle contraction
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: positive regulation of smooth muscle contraction is biologically
      consistent with the curated synthesis for Edn1 and is supported by ISO
      evidence (GO_REF:0000096).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon identifies ET-1 as a potent vasoconstrictor whose
        ETA signaling in vascular smooth muscle promotes sustained contraction.
- term:
    id: GO:0046888
    label: negative regulation of hormone secretion
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: negative regulation of hormone secretion is related to reported
      Edn1 biology only as a broad downstream readout or generic interaction
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0048237
    label: rough endoplasmic reticulum lumen
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: The local evidence supports Edn1 as a secreted peptide precursor,
      but does not verify a rough endoplasmic reticulum lumen localization.
    action: UNDECIDED
    reason: Secretory-protein biology alone is not enough to retain this specific
      automated cellular-component annotation without direct localization evidence.
- term:
    id: GO:0051899
    label: membrane depolarization
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: membrane depolarization is related to reported Edn1 biology only as
      a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0090023
    label: positive regulation of neutrophil chemotaxis
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: positive regulation of neutrophil chemotaxis is related to reported
      Edn1 biology only as a broad downstream readout or generic interaction
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:1901224
    label: positive regulation of non-canonical NF-kappaB signal transduction
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: positive regulation of non-canonical NF-kappaB signal transduction
      is related to reported Edn1 biology only as a broad downstream readout or
      generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:1904707
    label: positive regulation of vascular associated smooth muscle cell
      proliferation
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: positive regulation of vascular associated smooth muscle cell
      proliferation is related to reported Edn1 biology only as a broad
      downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:1900182
    label: positive regulation of protein localization to nucleus
  evidence_type: IMP
  original_reference_id: PMID:21525433
  review:
    summary: positive regulation of protein localization to nucleus is related
      to reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:1905653
    label: positive regulation of artery morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:20495147
  review:
    summary: positive regulation of artery morphogenesis is supported for Edn1
      in a tissue, developmental, trafficking, or disease-model context, but it
      is not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: PMID:9671575
      supporting_text: dHAND and the related gene, eHAND, are downregulated in
        the branchial and aortic arches of Edn1-null embryos.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:24722437
  review:
    summary: extracellular space is biologically consistent with the curated
      synthesis for Edn1 and is supported by IDA evidence (PMID:24722437).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon states that ET-1 functions as an extracellular
        ligand produced by endothelial and epithelial cells.
- term:
    id: GO:0048018
    label: receptor ligand activity
  evidence_type: IDA
  original_reference_id: PMID:24722437
  review:
    summary: receptor ligand activity is biologically consistent with the
      curated synthesis for Edn1 and is supported by IDA evidence
      (PMID:24722437).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
- term:
    id: GO:0086100
    label: endothelin receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:24722437
  review:
    summary: endothelin receptor signaling pathway is biologically consistent
      with the curated synthesis for Edn1 and is supported by IDA evidence
      (PMID:24722437).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core receptor binding and signaling: Endothelin stimulates
        high-affinity receptor binding and phospholipase C signaling in fibroblasts;
        the abstract reports that endothelin "specifically binds to a single class
        of high affinity receptors" and "stimulates phospholipase C with the production
        of second messengers inositol trisphosphate and 1,2-diacylglycerol."'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: 'Falcon summarizes the canonical endothelin receptor pathway:
        ET-1 activates ETA/ETB GPCRs with Gq/11-PLC-calcium/PKC and other downstream
        signaling.'
- term:
    id: GO:0003015
    label: heart process
  evidence_type: IMP
  original_reference_id: PMID:25197047
  review:
    summary: heart process is supported for Edn1 in a tissue, developmental,
      trafficking, or disease-model context, but it is not the core molecular
      role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: PMID:8152482
      supporting_text: have morphological abnormalities of the pharyngeal-arch-derived
        craniofacial tissues and organs.
- term:
    id: GO:0003015
    label: heart process
  evidence_type: IMP
  original_reference_id: PMID:31219639
  review:
    summary: heart process is supported for Edn1 in a tissue, developmental,
      trafficking, or disease-model context, but it is not the core molecular
      role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: PMID:23933587
      supporting_text: Edn1 and Ednra knock-out mice demonstrate abnormalities
        in pharyngeal arch artery patterning
- term:
    id: GO:0007411
    label: axon guidance
  evidence_type: IMP
  original_reference_id: PMID:30735130
  review:
    summary: axon guidance is supported for Edn1 in a tissue, developmental,
      trafficking, or disease-model context, but it is not the core molecular
      role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Sympathetic axon guidance: Venous endothelin-1 is a direct
        guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin
        controls growth and guidance of the STG axons to the heart."'
- term:
    id: GO:0008217
    label: regulation of blood pressure
  evidence_type: IMP
  original_reference_id: PMID:16868309
  review:
    summary: regulation of blood pressure is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0048675
    label: axon extension
  evidence_type: IDA
  original_reference_id: PMID:18401410
  review:
    summary: axon extension is supported for Edn1 in a tissue, developmental,
      trafficking, or disease-model context, but it is not the core molecular
      role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Sympathetic axon guidance: Venous endothelin-1 is a direct
        guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin
        controls growth and guidance of the STG axons to the heart."'
- term:
    id: GO:0000165
    label: MAPK cascade
  evidence_type: IDA
  original_reference_id: PMID:19111534
  review:
    summary: MAPK cascade is related to reported Edn1 biology only as a broad
      downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0000165
    label: MAPK cascade
  evidence_type: IMP
  original_reference_id: PMID:19111534
  review:
    summary: MAPK cascade is related to reported Edn1 biology only as a broad
      downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0044751
    label: cellular response to human chorionic gonadotropin stimulus
  evidence_type: IDA
  original_reference_id: PMID:19111534
  review:
    summary: cellular response to human chorionic gonadotropin stimulus is
      supported for Edn1 in a tissue, developmental, trafficking, or
      disease-model context, but it is not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: PMID:19111534
      supporting_text: The stimulatory effect of hCG on GVBD was partially blocked
        by the same antagonist.
- term:
    id: GO:0071372
    label: cellular response to follicle-stimulating hormone stimulus
  evidence_type: IDA
  original_reference_id: PMID:19111534
  review:
    summary: The cited oocyte paper supports LH/hCG-responsive Edn1 signaling,
      but does not directly establish a follicle-stimulating hormone response.
    action: UNDECIDED
    reason: Retaining this FSH-specific annotation requires evidence beyond the
      LH/hCG and ET-1/EDNRA oocyte-maturation results in the available citation.
- term:
    id: GO:0071373
    label: cellular response to luteinizing hormone stimulus
  evidence_type: IDA
  original_reference_id: PMID:19111534
  review:
    summary: cellular response to luteinizing hormone stimulus is supported for
      Edn1 in a tissue, developmental, trafficking, or disease-model context,
      but it is not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: PMID:19111534
      supporting_text: in response to the preovulatory luteinizing hormone (LH)/human
        chorionic gonadotropin (hCG) stimulation.
- term:
    id: GO:1903537
    label: meiotic cell cycle process involved in oocyte maturation
  evidence_type: IDA
  original_reference_id: PMID:19111534
  review:
    summary: meiotic cell cycle process involved in oocyte maturation is
      supported for Edn1 in a tissue, developmental, trafficking, or
      disease-model context, but it is not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: PMID:19111534
      supporting_text: treatment with endothelin-1 promoted oocyte GVBD.
- term:
    id: GO:0010467
    label: gene expression
  evidence_type: IDA
  original_reference_id: PMID:20929948
  review:
    summary: gene expression is supported for Edn1 in a tissue, developmental,
      trafficking, or disease-model context, but it is not the core molecular
      role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0070371
    label: ERK1 and ERK2 cascade
  evidence_type: IDA
  original_reference_id: PMID:20929948
  review:
    summary: ERK1 and ERK2 cascade is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0008217
    label: regulation of blood pressure
  evidence_type: IMP
  original_reference_id: PMID:20516397
  review:
    summary: regulation of blood pressure is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0010467
    label: gene expression
  evidence_type: IMP
  original_reference_id: PMID:20516397
  review:
    summary: gene expression is supported for Edn1 in a tissue, developmental,
      trafficking, or disease-model context, but it is not the core molecular
      role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0001569
    label: branching involved in blood vessel morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:23933587
  review:
    summary: branching involved in blood vessel morphogenesis is supported for
      Edn1 in a tissue, developmental, trafficking, or disease-model context,
      but it is not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: PMID:23933587
      supporting_text: Edn1/Ednra signaling is involved in pharyngeal artery
        development by controlling the fate of neural crest cells
- term:
    id: GO:0014033
    label: neural crest cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:23933587
  review:
    summary: neural crest cell differentiation is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: PMID:23933587
      supporting_text: controlling the fate of neural crest cells through a
        Dlx5/Dlx6-independent mechanism
- term:
    id: GO:0014034
    label: neural crest cell fate commitment
  evidence_type: IMP
  original_reference_id: PMID:23933587
  review:
    summary: neural crest cell fate commitment is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: PMID:23933587
      supporting_text: Edn1 and Ednra knock-out mice demonstrate abnormalities
        in pharyngeal arch artery patterning
- term:
    id: GO:0061626
    label: pharyngeal arch artery morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:23933587
  review:
    summary: pharyngeal arch artery morphogenesis is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: PMID:23933587
      supporting_text: Edn1 and Ednra knock-out mice demonstrate abnormalities
        in pharyngeal arch artery patterning
- term:
    id: GO:0070294
    label: renal sodium ion absorption
  evidence_type: IDA
  original_reference_id: PMID:23698114
  review:
    summary: renal sodium ion absorption is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Kidney and podocyte disease evidence: Endothelin-1 stimulation
        of primary mouse podocytes "elicited rapid calcium transients mediated by
        endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)"
        and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.'
- term:
    id: GO:0007005
    label: mitochondrion organization
  evidence_type: IDA
  original_reference_id: PMID:27899487
  review:
    summary: mitochondrion organization is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0030878
    label: thyroid gland development
  evidence_type: IMP
  original_reference_id: PMID:26506449
  review:
    summary: thyroid gland development is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: PMID:15110048
      supporting_text: ET-1/EdnrA signaling may contribute to the dorsoventral
        axis patterning of the branchial arch system
- term:
    id: GO:0001975
    label: response to amphetamine
  evidence_type: IMP
  original_reference_id: PMID:24875861
  review:
    summary: response to amphetamine is related to reported Edn1 biology only as
      a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0003253
    label: cardiac neural crest cell migration involved in outflow tract
      morphogenesis
  evidence_type: IDA
  original_reference_id: PMID:31219639
  review:
    summary: cardiac neural crest cell migration involved in outflow tract
      morphogenesis is supported for Edn1 in a tissue, developmental,
      trafficking, or disease-model context, but it is not the core molecular
      role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: PMID:31219639
      supporting_text: Cdc42 is part of the signaling pathway activated by endothelin
        specifically in OFT CNCC to control their migration.
- term:
    id: GO:0003357
    label: noradrenergic neuron differentiation
  evidence_type: IMP
  original_reference_id: PMID:24875861
  review:
    summary: noradrenergic neuron differentiation is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Sympathetic axon guidance: Venous endothelin-1 is a direct
        guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin
        controls growth and guidance of the STG axons to the heart."'
- term:
    id: GO:0006468
    label: protein phosphorylation
  evidence_type: IDA
  original_reference_id: PMID:31219639
  review:
    summary: protein phosphorylation captures the right general biology for
      Edn1, but a more specific GO term is available.
    action: MODIFY
    reason: The current term is too broad or less precise than endothelin
      receptor signaling pathway for this gene. Replace with endothelin receptor
      signaling pathway to align the annotation with the reviewed evidence.
    proposed_replacement_terms:
    - id: GO:0086100
      label: endothelin receptor signaling pathway
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0007507
    label: heart development
  evidence_type: IMP
  original_reference_id: PMID:24875861
  review:
    summary: heart development is supported for Edn1 in a tissue, developmental,
      trafficking, or disease-model context, but it is not the core molecular
      role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Cardiovascular development: Edn1-/- mice have "cardiovascular
        malformations including interrupted aortic arch ... and ventricular septal
        defect with abnormalities of the outflow tract."'
- term:
    id: GO:0010467
    label: gene expression
  evidence_type: IMP
  original_reference_id: PMID:30735130
  review:
    summary: gene expression is supported for Edn1 in a tissue, developmental,
      trafficking, or disease-model context, but it is not the core molecular
      role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0031175
    label: neuron projection development
  evidence_type: IDA
  original_reference_id: PMID:24875861
  review:
    summary: neuron projection development is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Sympathetic axon guidance: Venous endothelin-1 is a direct
        guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin
        controls growth and guidance of the STG axons to the heart."'
- term:
    id: GO:0035050
    label: embryonic heart tube development
  evidence_type: IMP
  original_reference_id: PMID:24875861
  review:
    summary: embryonic heart tube development is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Cardiovascular development: Edn1-/- mice have "cardiovascular
        malformations including interrupted aortic arch ... and ventricular septal
        defect with abnormalities of the outflow tract."'
- term:
    id: GO:0035050
    label: embryonic heart tube development
  evidence_type: IMP
  original_reference_id: PMID:30735130
  review:
    summary: embryonic heart tube development is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Cardiovascular development: Edn1-/- mice have "cardiovascular
        malformations including interrupted aortic arch ... and ventricular septal
        defect with abnormalities of the outflow tract."'
- term:
    id: GO:0035050
    label: embryonic heart tube development
  evidence_type: IMP
  original_reference_id: PMID:31219639
  review:
    summary: embryonic heart tube development is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Cardiovascular development: Edn1-/- mice have "cardiovascular
        malformations including interrupted aortic arch ... and ventricular septal
        defect with abnormalities of the outflow tract."'
- term:
    id: GO:0060385
    label: axonogenesis involved in innervation
  evidence_type: IMP
  original_reference_id: PMID:24875861
  review:
    summary: axonogenesis involved in innervation is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Sympathetic axon guidance: Venous endothelin-1 is a direct
        guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin
        controls growth and guidance of the STG axons to the heart."'
- term:
    id: GO:0060385
    label: axonogenesis involved in innervation
  evidence_type: IMP
  original_reference_id: PMID:30735130
  review:
    summary: axonogenesis involved in innervation is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Sympathetic axon guidance: Venous endothelin-1 is a direct
        guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin
        controls growth and guidance of the STG axons to the heart."'
- term:
    id: GO:0071526
    label: semaphorin-plexin signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:30735130
  review:
    summary: semaphorin-plexin signaling pathway is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0086100
    label: endothelin receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:31219639
  review:
    summary: endothelin receptor signaling pathway is biologically consistent
      with the curated synthesis for Edn1 and is supported by IDA evidence
      (PMID:31219639).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core receptor binding and signaling: Endothelin stimulates
        high-affinity receptor binding and phospholipase C signaling in fibroblasts;
        the abstract reports that endothelin "specifically binds to a single class
        of high affinity receptors" and "stimulates phospholipase C with the production
        of second messengers inositol trisphosphate and 1,2-diacylglycerol."'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: 'Falcon summarizes the canonical endothelin receptor pathway:
        ET-1 activates ETA/ETB GPCRs with Gq/11-PLC-calcium/PKC and other downstream
        signaling.'
- term:
    id: GO:0097492
    label: sympathetic neuron axon guidance
  evidence_type: IMP
  original_reference_id: PMID:30735130
  review:
    summary: sympathetic neuron axon guidance is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Sympathetic axon guidance: Venous endothelin-1 is a direct
        guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin
        controls growth and guidance of the STG axons to the heart."'
- term:
    id: GO:0003094
    label: glomerular filtration
  evidence_type: IDA
  original_reference_id: PMID:31402170
  review:
    summary: glomerular filtration is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Kidney and podocyte disease evidence: Endothelin-1 stimulation
        of primary mouse podocytes "elicited rapid calcium transients mediated by
        endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)"
        and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.'
- term:
    id: GO:0006366
    label: transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:27026367
  review:
    summary: transcription by RNA polymerase II is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0006874
    label: intracellular calcium ion homeostasis
  evidence_type: ISO
  original_reference_id: PMID:30990108
  review:
    summary: intracellular calcium ion homeostasis is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Kidney and podocyte disease evidence: Endothelin-1 stimulation
        of primary mouse podocytes "elicited rapid calcium transients mediated by
        endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)"
        and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.'
- term:
    id: GO:0006874
    label: intracellular calcium ion homeostasis
  evidence_type: IDA
  original_reference_id: PMID:30990108
  review:
    summary: intracellular calcium ion homeostasis is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Kidney and podocyte disease evidence: Endothelin-1 stimulation
        of primary mouse podocytes "elicited rapid calcium transients mediated by
        endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)"
        and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.'
- term:
    id: GO:0010467
    label: gene expression
  evidence_type: IDA
  original_reference_id: PMID:24722437
  review:
    summary: gene expression is supported for Edn1 in a tissue, developmental,
      trafficking, or disease-model context, but it is not the core molecular
      role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0060070
    label: canonical Wnt signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:24722437
  review:
    summary: canonical Wnt signaling pathway is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0070301
    label: cellular response to hydrogen peroxide
  evidence_type: ISO
  original_reference_id: PMID:30990108
  review:
    summary: cellular response to hydrogen peroxide is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0070588
    label: calcium ion transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:24722437
  review:
    summary: calcium ion transmembrane transport is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0072011
    label: glomerular endothelium development
  evidence_type: IDA
  original_reference_id: PMID:31402170
  review:
    summary: glomerular endothelium development is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Kidney and podocyte disease evidence: Endothelin-1 stimulation
        of primary mouse podocytes "elicited rapid calcium transients mediated by
        endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)"
        and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.'
- term:
    id: GO:0072112
    label: podocyte differentiation
  evidence_type: IDA
  original_reference_id: PMID:31402170
  review:
    summary: podocyte differentiation is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Kidney and podocyte disease evidence: Endothelin-1 stimulation
        of primary mouse podocytes "elicited rapid calcium transients mediated by
        endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)"
        and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models.'
- term:
    id: GO:0097237
    label: cellular response to toxic substance
  evidence_type: ISO
  original_reference_id: PMID:30990108
  review:
    summary: cellular response to toxic substance is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0097237
    label: cellular response to toxic substance
  evidence_type: IDA
  original_reference_id: PMID:30990108
  review:
    summary: cellular response to toxic substance is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0097237
    label: cellular response to toxic substance
  evidence_type: IMP
  original_reference_id: PMID:30990108
  review:
    summary: cellular response to toxic substance is related to reported Edn1
      biology only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0141156
    label: cAMP/PKA signal transduction
  evidence_type: ISO
  original_reference_id: PMID:30990108
  review:
    summary: cAMP/PKA signal transduction is related to reported Edn1 biology
      only as a broad downstream readout or generic interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:2001259
    label: positive regulation of cation channel activity
  evidence_type: ISO
  original_reference_id: PMID:30990108
  review:
    summary: positive regulation of cation channel activity is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0031583
    label: phospholipase D-activating G protein-coupled receptor signaling
      pathway
  evidence_type: IDA
  original_reference_id: PMID:8978712
  review:
    summary: phospholipase D-activating G protein-coupled receptor signaling
      pathway is supported for Edn1 in a tissue, developmental, trafficking, or
      disease-model context, but it is not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core receptor binding and signaling: Endothelin stimulates
        high-affinity receptor binding and phospholipase C signaling in fibroblasts;
        the abstract reports that endothelin "specifically binds to a single class
        of high affinity receptors" and "stimulates phospholipase C with the production
        of second messengers inositol trisphosphate and 1,2-diacylglycerol."'
- term:
    id: GO:0009953
    label: dorsal/ventral pattern formation
  evidence_type: IMP
  original_reference_id: PMID:15110048
  review:
    summary: dorsal/ventral pattern formation is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: PMID:15110048
      supporting_text: ET-1/EdnrA signaling may contribute to the dorsoventral
        axis patterning of the branchial arch system
- term:
    id: GO:0086100
    label: endothelin receptor signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: endothelin receptor signaling pathway is biologically consistent
      with the curated synthesis for Edn1 and is supported by ISS evidence
      (GO_REF:0000024).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core receptor binding and signaling: Endothelin stimulates
        high-affinity receptor binding and phospholipase C signaling in fibroblasts;
        the abstract reports that endothelin "specifically binds to a single class
        of high affinity receptors" and "stimulates phospholipase C with the production
        of second messengers inositol trisphosphate and 1,2-diacylglycerol."'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: 'Falcon summarizes the canonical endothelin receptor pathway:
        ET-1 activates ETA/ETB GPCRs with Gq/11-PLC-calcium/PKC and other downstream
        signaling.'
- term:
    id: GO:0010827
    label: regulation of D-glucose transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:11546805
  review:
    summary: regulation of D-glucose transmembrane transport is supported for
      Edn1 in a tissue, developmental, trafficking, or disease-model context,
      but it is not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0007193
    label: adenylate cyclase-inhibiting G protein-coupled receptor signaling
      pathway
  evidence_type: IGI
  original_reference_id: PMID:15632412
  review:
    summary: adenylate cyclase-inhibiting G protein-coupled receptor signaling
      pathway is supported for Edn1 in a tissue, developmental, trafficking, or
      disease-model context, but it is not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core receptor binding and signaling: Endothelin stimulates
        high-affinity receptor binding and phospholipase C signaling in fibroblasts;
        the abstract reports that endothelin "specifically binds to a single class
        of high affinity receptors" and "stimulates phospholipase C with the production
        of second messengers inositol trisphosphate and 1,2-diacylglycerol."'
- term:
    id: GO:0007193
    label: adenylate cyclase-inhibiting G protein-coupled receptor signaling
      pathway
  evidence_type: IDA
  original_reference_id: PMID:2542249
  review:
    summary: adenylate cyclase-inhibiting G protein-coupled receptor signaling
      pathway is supported for Edn1 in a tissue, developmental, trafficking, or
      disease-model context, but it is not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core receptor binding and signaling: Endothelin stimulates
        high-affinity receptor binding and phospholipase C signaling in fibroblasts;
        the abstract reports that endothelin "specifically binds to a single class
        of high affinity receptors" and "stimulates phospholipase C with the production
        of second messengers inositol trisphosphate and 1,2-diacylglycerol."'
- term:
    id: GO:0035810
    label: positive regulation of urine volume
  evidence_type: IMP
  original_reference_id: PMID:15632412
  review:
    summary: positive regulation of urine volume is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0035810
    label: positive regulation of urine volume
  evidence_type: IGI
  original_reference_id: PMID:15632412
  review:
    summary: positive regulation of urine volume is supported for Edn1 in a
      tissue, developmental, trafficking, or disease-model context, but it is
      not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0035815
    label: positive regulation of renal sodium excretion
  evidence_type: IMP
  original_reference_id: PMID:15314687
  review:
    summary: positive regulation of renal sodium excretion is supported for Edn1
      in a tissue, developmental, trafficking, or disease-model context, but it
      is not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0006885
    label: regulation of pH
  evidence_type: IDA
  original_reference_id: PMID:11413164
  review:
    summary: regulation of pH is supported for Edn1 in a tissue, developmental,
      trafficking, or disease-model context, but it is not the core molecular
      role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0001501
    label: skeletal system development
  evidence_type: IMP
  original_reference_id: PMID:8152482
  review:
    summary: skeletal system development is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Cardiovascular development: Edn1-/- mice have "cardiovascular
        malformations including interrupted aortic arch ... and ventricular septal
        defect with abnormalities of the outflow tract."'
- term:
    id: GO:0001569
    label: branching involved in blood vessel morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:7615798
  review:
    summary: branching involved in blood vessel morphogenesis is supported for
      Edn1 in a tissue, developmental, trafficking, or disease-model context,
      but it is not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Cardiovascular development: Edn1-/- mice have "cardiovascular
        malformations including interrupted aortic arch ... and ventricular septal
        defect with abnormalities of the outflow tract."'
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: IMP
  original_reference_id: PMID:8764295
  review:
    summary: response to hypoxia is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IDA
  original_reference_id: PMID:2542249
  review:
    summary: signaling receptor binding captures the right general biology for
      Edn1, but a more specific GO term is available.
    action: MODIFY
    reason: The current term is too broad or less precise than receptor ligand
      activity for this gene. Replace with receptor ligand activity to align the
      annotation with the reviewed evidence.
    proposed_replacement_terms:
    - id: GO:0048018
      label: receptor ligand activity
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IDA
  original_reference_id: PMID:8680799
  review:
    summary: signaling receptor binding captures the right general biology for
      Edn1, but a more specific GO term is available.
    action: MODIFY
    reason: The current term is too broad or less precise than receptor ligand
      activity for this gene. Replace with receptor ligand activity to align the
      annotation with the reviewed evidence.
    proposed_replacement_terms:
    - id: GO:0048018
      label: receptor ligand activity
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
- term:
    id: GO:0007200
    label: phospholipase C-activating G protein-coupled receptor signaling
      pathway
  evidence_type: IDA
  original_reference_id: PMID:2542249
  review:
    summary: phospholipase C-activating G protein-coupled receptor signaling
      pathway captures the right general biology for Edn1, but a more specific
      GO term is available.
    action: MODIFY
    reason: The current term is too broad or less precise than endothelin
      receptor signaling pathway for this gene. Replace with endothelin receptor
      signaling pathway to align the annotation with the reviewed evidence.
    proposed_replacement_terms:
    - id: GO:0086100
      label: endothelin receptor signaling pathway
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core receptor binding and signaling: Endothelin stimulates
        high-affinity receptor binding and phospholipase C signaling in fibroblasts;
        the abstract reports that endothelin "specifically binds to a single class
        of high affinity receptors" and "stimulates phospholipase C with the production
        of second messengers inositol trisphosphate and 1,2-diacylglycerol."'
- term:
    id: GO:0007507
    label: heart development
  evidence_type: IMP
  original_reference_id: PMID:7615798
  review:
    summary: heart development is supported for Edn1 in a tissue, developmental,
      trafficking, or disease-model context, but it is not the core molecular
      role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Cardiovascular development: Edn1-/- mice have "cardiovascular
        malformations including interrupted aortic arch ... and ventricular septal
        defect with abnormalities of the outflow tract."'
- term:
    id: GO:0008217
    label: regulation of blood pressure
  evidence_type: IMP
  original_reference_id: PMID:8152482
  review:
    summary: regulation of blood pressure is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IDA
  original_reference_id: PMID:2542249
  review:
    summary: positive regulation of cell population proliferation is related to
      reported Edn1 biology only as a broad downstream readout or generic
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This overstates the direct role of the gene product; the curated
      model is better captured by the specific receptor/ligand, pathway, and
      supported non-core phenotype terms.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0014032
    label: neural crest cell development
  evidence_type: IMP
  original_reference_id: PMID:9671575
  review:
    summary: neural crest cell development is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: PMID:9671575
      supporting_text: A signaling cascade involving endothelin-1, dHAND and
        msx1 regulates development of neural-crest-derived branchial arch mesenchyme.
- term:
    id: GO:0042474
    label: middle ear morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:8152482
  review:
    summary: The available local evidence supports pharyngeal-arch-derived
      craniofacial abnormalities but does not directly verify middle ear
      morphogenesis.
    action: UNDECIDED
    reason: Retaining this specific developmental annotation requires direct
      middle-ear evidence rather than generic pharyngeal arch or cardiovascular
      phenotype support.
- term:
    id: GO:0043179
    label: rhythmic excitation
  evidence_type: IMP
  original_reference_id: PMID:8764295
  review:
    summary: rhythmic excitation is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0045987
    label: positive regulation of smooth muscle contraction
  evidence_type: IDA
  original_reference_id: PMID:8010105
  review:
    summary: positive regulation of smooth muscle contraction is biologically
      consistent with the curated synthesis for Edn1 and is supported by IDA
      evidence (PMID:8010105).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon identifies ET-1 as a potent vasoconstrictor whose
        ETA signaling in vascular smooth muscle promotes sustained contraction.
- term:
    id: GO:0048514
    label: blood vessel morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:7615798
  review:
    summary: blood vessel morphogenesis is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Cardiovascular development: Edn1-/- mice have "cardiovascular
        malformations including interrupted aortic arch ... and ventricular septal
        defect with abnormalities of the outflow tract."'
- term:
    id: GO:0051216
    label: cartilage development
  evidence_type: IMP
  original_reference_id: PMID:8152482
  review:
    summary: cartilage development is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Cardiovascular development: Edn1-/- mice have "cardiovascular
        malformations including interrupted aortic arch ... and ventricular septal
        defect with abnormalities of the outflow tract."'
- term:
    id: GO:0001701
    label: in utero embryonic development
  evidence_type: IMP
  original_reference_id: PMID:15327783
  review:
    summary: in utero embryonic development is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Cardiovascular development: Edn1-/- mice have "cardiovascular
        malformations including interrupted aortic arch ... and ventricular septal
        defect with abnormalities of the outflow tract."'
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:15314687
  review:
    summary: extracellular space is biologically consistent with the curated
      synthesis for Edn1 and is supported by IDA evidence (PMID:15314687).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon states that ET-1 functions as an extracellular
        ligand produced by endothelial and epithelial cells.
- term:
    id: GO:0007589
    label: body fluid secretion
  evidence_type: IMP
  original_reference_id: PMID:15314687
  review:
    summary: body fluid secretion is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0008217
    label: regulation of blood pressure
  evidence_type: IMP
  original_reference_id: PMID:15314687
  review:
    summary: regulation of blood pressure is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0014032
    label: neural crest cell development
  evidence_type: IMP
  original_reference_id: PMID:15327783
  review:
    summary: neural crest cell development is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Cardiovascular development: Edn1-/- mice have "cardiovascular
        malformations including interrupted aortic arch ... and ventricular septal
        defect with abnormalities of the outflow tract."'
- term:
    id: GO:0031707
    label: endothelin A receptor binding
  evidence_type: IPI
  original_reference_id: PMID:9449664
  review:
    summary: endothelin A receptor binding is biologically consistent with the
      curated synthesis for Edn1 and is supported by IPI evidence
      (PMID:9449664).
    action: ACCEPT
    reason: The term matches a direct molecular function, pathway, or
      location/physiological output of Edn1; it is specific enough to retain
      without replacement.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
        to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
        EDNRA and EDNRB.'
    - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
      supporting_text: Falcon reports that mature ET-1 signals through ETA/EDNRA
        receptors, supporting endothelin A receptor binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12441350
  review:
    summary: protein binding is not supported as an appropriate annotation for
      Edn1 after review of the available mouse evidence.
    action: REMOVE
    reason: The term appears to reflect either an unsupported transfer, a
      paralog/family overreach, or a localization/process inconsistent with the
      curated Edn1 biology.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Curation judgment: broad signaling outputs such as MAPK, ERK,
        JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance
        response, hypoxia response, and many hormone-response terms are downstream
        or context-specific readouts of endothelin receptor activation.'
- term:
    id: GO:0007585
    label: respiratory gaseous exchange by respiratory system
  evidence_type: IMP
  original_reference_id: PMID:10626068
  review:
    summary: respiratory gaseous exchange by respiratory system is supported for
      Edn1 in a tissue, developmental, trafficking, or disease-model context,
      but it is not the core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0008217
    label: regulation of blood pressure
  evidence_type: IMP
  original_reference_id: PMID:10626068
  review:
    summary: regulation of blood pressure is supported for Edn1 in a tissue,
      developmental, trafficking, or disease-model context, but it is not the
      core molecular role.
    action: KEEP_AS_NON_CORE
    reason: This annotation captures a real downstream or context-specific
      consequence of Edn1 activity. It should be retained as non-core so it does
      not obscure the primary receptor/ligand signaling function.
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
- term:
    id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:11546805
  review:
    summary: G protein-coupled receptor signaling pathway captures the right
      general biology for Edn1, but a more specific GO term is available.
    action: MODIFY
    reason: The current term is too broad or less precise than endothelin
      receptor signaling pathway for this gene. Replace with endothelin receptor
      signaling pathway to align the annotation with the reviewed evidence.
    proposed_replacement_terms:
    - id: GO:0086100
      label: endothelin receptor signaling pathway
    supported_by:
    - reference_id: file:mouse/Edn1/Edn1-notes.md
      supporting_text: 'Vascular and blood-pressure physiology: Edn1-null mice "die
        of respiratory failure at birth and have morphological abnormalities of the
        pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop
        elevated blood pressure."'
references:
- id: file:mouse/Edn1/Edn1-notes.md
  title: Curator notes for mouse Edn1 review
- id: file:mouse/Edn1/Edn1-deep-research-falcon.md
  title: Falcon deep research report for mouse Edn1
- id: file:mouse/Edn1/Edn1-uniprot.txt
  title: UniProtKB record for mouse Edn1
- id: file:mouse/Edn1/Edn1-goa.tsv
  title: QuickGO export for mouse Edn1
- 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:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  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: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:10626068
  title: Endothelin in the central control of cardiovascular and respiratory
    functions.
  findings: []
- id: PMID:11413164
  title: Endothelin-1/endothelin-B receptor-mediated increases in NHE3 activity
    in chronic metabolic acidosis.
  findings: []
- id: PMID:11546805
  title: beta -Arrestin-mediated recruitment of the Src family kinase Yes
    mediates endothelin-1-stimulated glucose transport.
  findings: []
- id: PMID:12441350
  title: The first inner loop of endothelin receptor type B is necessary for
    specific coupling to Galpha 13.
  findings: []
- id: PMID:15110048
  title: Endothelin-1 regulates the dorsoventral branchial arch patterning in
    mice.
  findings: []
- id: PMID:15314687
  title: Collecting duct-specific knockout of endothelin-1 causes hypertension
    and sodium retention.
  findings: []
- id: PMID:15327783
  title: Temporal requirement of signaling cascade involving
    endothelin-1/endothelin receptor type A in branchial arch development.
  findings: []
- id: PMID:15632412
  title: Collecting duct-specific knockout of endothelin-1 alters vasopressin
    regulation of urine osmolality.
  findings: []
- id: PMID:16868309
  title: Collecting duct-specific knockout of the endothelin B receptor causes
    hypertension and sodium retention.
  findings: []
- id: PMID:18401410
  title: Endothelins are vascular-derived axonal guidance cues for developing
    sympathetic neurons.
  findings: []
- id: PMID:19111534
  title: Paracrine regulation of the resumption of oocyte meiosis by
    endothelin-1.
  findings: []
- id: PMID:20495147
  title: NFATc3 contributes to intermittent hypoxia-induced arterial remodeling
    in mice.
  findings: []
- id: PMID:20516397
  title: Low blood pressure in endothelial cell-specific endothelin 1 knockout
    mice.
  findings: []
- id: PMID:20929948
  title: Endothelin receptor type A expression defines a distinct cardiac
    subdomain within the heart field and is later implicated in chamber
    myocardium formation.
  findings: []
- id: PMID:21525433
  title: Endothelin-1 contributes to increased NFATc3 activation by chronic
    hypoxia in pulmonary arteries.
  findings: []
- id: PMID:23698114
  title: Endothelin-1 inhibits sodium reabsorption by ET(A) and ET(B) receptors
    in the mouse cortical collecting duct.
  findings: []
- id: PMID:23933587
  title: Endothelin regulates neural crest deployment and fate to form great
    vessels through Dlx5/Dlx6-independent mechanisms.
  findings: []
- id: PMID:24722437
  title: Direct action of endothelin-1 on podocytes promotes diabetic
    glomerulosclerosis.
  findings: []
- id: PMID:24875861
  title: Venous endothelin guides sympathetic innervation of the developing
    mouse heart.
  findings: []
- id: PMID:25197047
  title: Essential role of sympathetic endothelin A receptors for adverse
    cardiac remodeling.
  findings: []
- id: PMID:2542249
  title: A novel vasoactive peptide endothelin stimulates mitogenesis through
    inositol lipid turnover in Swiss 3T3 fibroblasts.
  findings: []
- id: PMID:26506449
  title: Postotic and preotic cranial neural crest cells differently contribute
    to thyroid development.
  findings: []
- id: PMID:27026367
  title: Endothelin-1 Induces Proteinuria by Heparanase-Mediated Disruption of
    the Glomerular Glycocalyx.
  findings: []
- id: PMID:27899487
  title: Glomerular Endothelial Mitochondrial Dysfunction Is Essential and
    Characteristic of Diabetic Kidney Disease Susceptibility.
  findings: []
- id: PMID:30735130
  title: Venous endothelin modulates responsiveness of cardiac sympathetic axons
    to arterial semaphorin.
  findings: []
- id: PMID:30990108
  title: 'ET(A)R and protein kinase A pathway mediate ET-1 sensitization of TRPA1
    channel: A molecular mechanism of ET-1-induced mechanical hyperalgesia.'
  findings: []
- id: PMID:31219639
  title: Cdc42 activation by endothelin regulates neural crest cell migration in
    the cardiac outflow tract.
  findings: []
- id: PMID:31402170
  title: Endothelin receptor-A mediates degradation of the glomerular
    endothelial surface layer via pathologic crosstalk between activated
    podocytes and glomerular endothelial cells.
  findings: []
- id: PMID:7615798
  title: Aortic arch malformations and ventricular septal defect in mice
    deficient in endothelin-1.
  findings: []
- id: PMID:8010105
  title: Effects of endothelin-1 on isolated uterine horns in estrogen-primed
    and pregnant mice.
  findings: []
- id: PMID:8152482
  title: Elevated blood pressure and craniofacial abnormalities in mice
    deficient in endothelin-1.
  findings: []
- id: PMID:8680799
  title: Developmental changes in cerebellar endothelin-1 receptors in the
    neurologic mouse lurcher mutant.
  findings: []
- id: PMID:8764295
  title: Impaired ventilatory responses to hypoxia and hypercapnia in mutant
    mice deficient in endothelin-1.
  findings: []
- id: PMID:8978712
  title: Endothelin stimulates phospholipase D in striatal astrocytes.
  findings: []
- id: PMID:9449664
  title: Cranial and cardiac neural crest defects in endothelin-A
    receptor-deficient mice.
  findings: []
- id: PMID:9671575
  title: A signaling cascade involving endothelin-1, dHAND and msx1 regulates
    development of neural-crest-derived branchial arch mesenchyme.
  findings: []
core_functions:
- description: Mature endothelin-1 is a secreted peptide receptor ligand that
    binds endothelin A and B receptors to activate endothelin receptor signaling
    and regulate vascular tone, smooth muscle contraction, and blood-pressure
    physiology.
  molecular_function:
    id: GO:0048018
    label: receptor ligand activity
  directly_involved_in:
  - id: GO:0086100
    label: endothelin receptor signaling pathway
  - id: GO:0003100
    label: regulation of systemic arterial blood pressure by endothelin
  - id: GO:0045987
    label: positive regulation of smooth muscle contraction
  locations:
  - id: GO:0005615
    label: extracellular space
  supported_by:
  - reference_id: file:mouse/Edn1/Edn1-notes.md
    supporting_text: 'Core ligand identity: Edn1 encodes preproendothelin-1, processed
      to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors
      EDNRA and EDNRB.'
  - reference_id: file:mouse/Edn1/Edn1-deep-research-falcon.md
    supporting_text: Falcon reinforces the core model that mature ET-1 is a
      secreted peptide ligand for ETA/EDNRA and ETB/EDNRB receptors, driving
      endothelin receptor signaling, vascular tone, and blood-pressure
      physiology.
proposed_new_terms: []
suggested_questions:
- question: For Edn1, should developmental axon-guidance and neural-crest roles
    be grouped under endothelin receptor signaling rather than maintained as
    multiple granular phenotype-like GO process annotations?
suggested_experiments:
- hypothesis: Different Edn1 GO process annotations reflect receptor- and
    tissue-specific deployment of the same secreted ligand.
  description: Compare Ednra- and Ednrb-dependent responses to mature ET-1 in
    vascular smooth muscle, podocytes, and sympathetic neurons using
    receptor-selective antagonists or conditional receptor knockouts.
  experiment_type: receptor-specific ligand response assay

Edn1

Gene Description

Existing Annotations Review

Core Functions

Mature endothelin-1 is a secreted peptide receptor ligand that binds endothelin A and B receptors to activate endothelin receptor signaling and regulate vascular tone, smooth muscle contraction, and blood-pressure physiology.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

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: Mouse Edn1 (UniProt P22387) — functional annotation of Endothelin-1 (ET-1)

0) Target verification (critical disambiguation)

1) Key concepts and definitions (current understanding)

1.1 What Edn1 encodes

1.2 Biosynthesis and peptide processing: prepro → big ET-1 → ET-1

1.3 Receptors and canonical pathway definition

2) Molecular function, signaling mechanisms, and localization

2.1 Subcellular/extracellular localization and secretion

2.2 Downstream signaling pathways (ETA/ETB)

3) In vivo physiological roles in mouse: primary functional annotation

3.1 Adult physiology: vascular tone and renal endothelin system

3.2 Embryonic development: Edn1 as a pharyngeal-arch morphogen for craniofacial patterning

4) Recent developments (prioritizing 2023–2024) and real-world implementations

4.1 Drug development and clinical implementation (endothelin pathway targeting)

4.2 Biomarkers and human tissue evidence supporting endothelin-axis targeting

5) Quantitative/statistical highlights from recent studies (selected)

6) Expert opinions and analysis (authoritative synthesis)

7) Summary table for functional annotation (mouse Edn1)

8) Visual evidence (kidney localization and single-cell expression)

9) Scope notes / limitations

Citations

Notes

Edn1 curation notes

Evidence synthesis

📄 View Raw YAML