NTN1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	IBA GO_REF:0000033	REMOVE	Summary: The POU-seeded DNA-binding-function transfer does not fit the netrin protein. Reason: The GOA source PTN000180816 has POU-transcription-factor experimental seeds, whereas the target has the laminin/EGF/NTR architecture and netrin receptor-ligand biology. The current PTHR10574 PAINT cache contains these POU-seeded rows, so the original claim of a demonstrated wrong-family tree placement is replaced by a provenance discrepancy requiring upstream inspection. These specific Pol II sequence-recognition/TF activities are not supported by the target architecture or source-to-target functional homology; removal is not based on secreted localization alone. PMID:22871610 demonstrates a truncated nucleolar NTN1 form associated with ribosomal-gene promoters; that finding concerns ribosome biogenesis and does not establish these Pol II-specific activities. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000180816 · PTN000180816 SUPPORTS SOURCE BUT NOT TARGET The POU-seeded IBD rows are present in the cached PTHR10574 export; the target netrin domain architecture does not support inheritance of POU sequence-specific DNA recognition. Exact tree association/assembly requires upstream verification. Supporting Evidence: file:human/NTN1/NTN1-uniprot.txt Netrins control guidance of CNS commissural axons
GO:0006357 regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	UNDECIDED	Summary: Pol II transcription regulation must be evaluated independently of POU DNA-binding activity. Reason: A receptor ligand can regulate transcription through signaling, and secretion does not exclude an additional intracellular molecular form. The POU-seeded source at PTN000180816 does not establish the relevant netrin-specific mechanism, but failure of that trace is not proof that this broader biological process is impossible. No direct target-specific participation in Pol II regulation was established in this re-review. PMID:22871610 demonstrates a truncated nucleolar NTN1 form associated with ribosomal-gene promoters; that finding concerns ribosome biogenesis and does not establish these Pol II-specific activities. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000180816 · PTN000180816 UNRESOLVED The POU source-to-netrin connection is not explained by the cached IBD export. Independent netrin-specific regulation of Pol II remains unresolved and cannot be excluded by primary extracellular localization. Supporting Evidence: file:human/NTN1/NTN1-uniprot.txt Netrins control guidance of CNS commissural axons
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA GO_REF:0000033	REMOVE	Summary: The POU-seeded DNA-binding-function transfer does not fit the netrin protein. Reason: The GOA source PTN000180816 has POU-transcription-factor experimental seeds, whereas the target has the laminin/EGF/NTR architecture and netrin receptor-ligand biology. The current PTHR10574 PAINT cache contains these POU-seeded rows, so the original claim of a demonstrated wrong-family tree placement is replaced by a provenance discrepancy requiring upstream inspection. These specific Pol II sequence-recognition/TF activities are not supported by the target architecture or source-to-target functional homology; removal is not based on secreted localization alone. PMID:22871610 demonstrates a truncated nucleolar NTN1 form associated with ribosomal-gene promoters; that finding concerns ribosome biogenesis and does not establish these Pol II-specific activities. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000180816 · PTN000180816 SUPPORTS SOURCE BUT NOT TARGET The POU-seeded IBD rows are present in the cached PTHR10574 export; the target netrin domain architecture does not support inheritance of POU sequence-specific DNA recognition. Exact tree association/assembly requires upstream verification. Supporting Evidence: file:human/NTN1/NTN1-uniprot.txt Netrins control guidance of CNS commissural axons
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: Correct annotation. NTN1 encodes a secreted protein with a signal peptide (residues 1-24). UniProt confirms subcellular location as "Secreted" and notes it is "Mainly secreted." This is consistent with its function as an extracellular axon guidance cue. Reason: Core localization for NTN1 function. Netrin-1 is primarily a secreted protein that functions in the extracellular space as a diffusible guidance cue. Supporting Evidence: PMID:28945198 Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. UniProt:O95631 Note=Mainly secreted
GO:0005737 cytoplasm	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Acceptable annotation. While NTN1 is primarily secreted, UniProt confirms cytoplasmic localization, particularly for mutant forms that fail to be secreted. PMID:28945198 shows that pathogenic NTN1 variants are "almost exclusively detected in the intracellular compartment" rather than being secreted normally. Reason: Secondary localization. The protein is primarily secreted but can be detected in cytoplasm, especially for mutant variants that have defective secretion. Supporting Evidence: PMID:28945198 the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments.
GO:0006915 apoptotic process	IEA GO_REF:0000043	MODIFY	Summary: Acceptable but imprecise annotation. NTN1 functions as a survival factor that prevents initiation of apoptosis through its receptors. UniProt notes it is "Involved in tumorigenesis by regulating apoptosis." However, the term "apoptotic process" is too general - NTN1 acts as a negative regulator of apoptosis. Reason: The annotation captures involvement in apoptosis but lacks directionality. NTN1 serves as a survival factor that prevents apoptosis initiation. A more specific term would better reflect its anti-apoptotic function. Proposed replacements: negative regulation of apoptotic process
GO:0005515 protein binding	IPI PMID:19721007 Netrin-1 up-regulation in inflammatory bowel diseases is req...	MODIFY	Summary: Generic protein binding annotation. NTN1 binds to multiple receptor proteins including DCC, UNC5 family members, and DSCAM. However, "protein binding" is uninformative. The specific binding partner would be DCC based on the reference. Reason: While NTN1 does bind proteins (its receptors), the generic "protein binding" term is uninformative. The more specific netrin receptor binding term better captures the receptor-ligand function. Proposed replacements: netrin receptor binding Supporting Evidence: file:human/NTN1/NTN1-deep-research-falcon.md NTN1 is summarized as a secreted extracellular ligand that signals through dependence receptors including DCC, NEO1, and UNC5-family receptors.
GO:0005515 protein binding	IPI PMID:20434207 Transmembrane receptor DCC associates with protein synthesis...	MODIFY	Summary: Generic protein binding annotation based on interaction with DCC receptor. The reference describes DCC-netrin interaction in context of translation regulation. Reason: While the protein-protein interaction is valid, "protein binding" is uninformative. The specific DCC receptor binding would be more appropriate. Proposed replacements: netrin receptor binding Supporting Evidence: file:human/NTN1/NTN1-deep-research-falcon.md The report supports Netrin-1 receptor-ligand function through DCC, NEO1, and UNC5-family dependence receptors.
GO:0005515 protein binding	IPI PMID:26190107 A Floor-Plate Extracellular Protein-Protein Interaction Scre...	REMOVE	Summary: The interaction is retained as evidence but generic protein binding is not informative. Reason: The experimental interaction need not be disputed; the broad term is removed under the project convention for uninformative protein-binding annotations. Receptor-binding and guidance annotations carry the informative molecular context.
GO:0005515 protein binding	IPI PMID:28501620 Molecular characterization of Netrin-1 and APP receptor bind...	REMOVE	Summary: The interaction is retained as evidence but generic protein binding is not informative. Reason: The experimental interaction need not be disputed; the broad term is removed under the project convention for uninformative protein-binding annotations. Receptor-binding and guidance annotations carry the informative molecular context.
GO:0005604 basement membrane	IEA GO_REF:0000107	ACCEPT	Summary: Basement-membrane-associated netrin is consistent with its core substrate-guidance mechanism. Reason: Mouse studies directly place netrin1 on the pial surface as a local axon-growth substrate (PMID:28780049). Basement-membrane/ECM association is part of netrin guidance biology, not a competing alternative to extracellular localization; the earlier rationale demoting it because extracellular region was primary was incorrect. Supporting Evidence: PMID:28780049 deposited on the pial surface as a haptotactic adhesive substrate
GO:0045202 synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Acceptable localization based on ortholog transfer. Netrin-1 plays roles in synapse formation and synaptic connectivity during neural development. Reason: Secondary localization relevant to NTN1's role in neural development and synapse assembly regulation.
GO:0051963 regulation of synapse assembly	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Acceptable annotation based on ortholog transfer from mouse. Netrin-1 is known to regulate synapse formation during neural development through its guidance functions. Reason: Downstream consequence of NTN1's axon guidance function. Synapse assembly is affected by proper axon pathfinding and target recognition.
GO:0061643 chemorepulsion of axon	IEA GO_REF:0000107	ACCEPT	Summary: Core function annotation. NTN1 mediates axon chemorepulsion when bound to UNC5 receptors. UniProt notes "Binding to UNC5C might cause dissociation of UNC5C from polymerized TUBB3 in microtubules and thereby lead to increased microtubule dynamics and axon repulsion." Reason: Core function of NTN1. Axon chemorepulsion is mediated through UNC5 receptor binding and is essential for proper axon pathfinding.
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Acceptable but potentially overly specific localization. This is based on ortholog transfer from mouse. Netrin-1 may be present at glutamatergic synapses but this specificity may be overly detailed for an IEA annotation. Reason: Secondary localization. While NTN1 may be present at glutamatergic synapses, this is a very specific localization that may require direct experimental validation.
GO:0005829 cytosol	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Acceptable annotation based on immunofluorescence data from HPA. While NTN1 is primarily secreted, intracellular detection is expected for proteins in transit through the secretory pathway. Reason: Secondary localization. The protein is primarily secreted but can be detected in cytosol, consistent with transit through the secretory pathway.
GO:0005576 extracellular region	IDA PMID:28945198 Mutations in the netrin-1 gene cause congenital mirror movem...	ACCEPT	Summary: Core localization annotation with direct experimental evidence. PMID:28945198 directly demonstrates that wild-type netrin-1 is secreted and detected in extracellular compartments, while pathogenic mutants are retained intracellularly. Reason: Core localization with strong experimental support. The secretion of NTN1 is essential for its function as an extracellular guidance cue. Supporting Evidence: PMID:28945198 the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments.
GO:0061643 chemorepulsion of axon	ISS GO_REF:0000024	ACCEPT	Summary: Core function annotation transferred from mouse ortholog. Axon chemorepulsion through UNC5 receptors is a well-established function of netrins conserved across species. Reason: Core function of NTN1. Axon chemorepulsion is a conserved netrin function mediated through UNC5 receptor binding.
GO:0006930 substrate-dependent cell migration, cell extension	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Acceptable annotation. Netrin-1 influences cell migration and extension through its guidance functions. This is downstream of receptor binding and signaling. Reason: Secondary biological process. Cell migration effects are downstream of NTN1's primary guidance function through receptor binding.
GO:0007265 Ras protein signal transduction	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Downstream signaling annotation. Netrin-1 receptor binding triggers intracellular signaling cascades including Ras pathway activation. This is part of the downstream response to netrin binding, not a direct function of NTN1 itself. Reason: Downstream signaling consequence. NTN1 does not directly participate in Ras signaling but triggers it through receptor activation.
GO:0032488 Cdc42 protein signal transduction	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Downstream signaling annotation. Netrin-1 binding to DCC triggers Cdc42 activation as part of the cytoskeletal remodeling response. Reactome pathway R-HSA-418850 describes "Activation of Cdc42" in netrin signaling. Reason: Downstream signaling consequence. NTN1 triggers Cdc42 signaling through DCC receptor activation, leading to cytoskeletal changes for axon guidance.
GO:0045773 positive regulation of axon extension	ISS GO_REF:0000024	ACCEPT	Summary: Core function annotation. Netrin-1 promotes axon extension through DCC receptor signaling, complementing its chemoattraction and chemorepulsion functions. This is a well-established core function of netrins. Reason: Core function of NTN1. Positive regulation of axon extension through DCC receptor is a fundamental netrin function in axon guidance.
GO:2000147 positive regulation of cell motility	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Acceptable annotation. Netrin-1 promotes cell motility through its guidance functions. This is a broader consequence of its chemotactic activity. Reason: Secondary biological process. Cell motility regulation is downstream of NTN1's primary receptor-mediated guidance functions.
GO:0005576 extracellular region	TAS Reactome:R-HSA-373707	ACCEPT	Summary: Correct localization annotation from Reactome pathway "Netrin-1 induced DCC clustering". NTN1 functions extracellularly where it binds DCC receptors. Reason: Core localization. Extracellular region is the functional location for NTN1's role in receptor binding and axon guidance.
GO:0005576 extracellular region	TAS Reactome:R-HSA-373711	ACCEPT	Summary: Correct localization annotation from Reactome pathway "DCC interaction with Netrin-1". NTN1 is secreted and functions extracellularly. Reason: Core localization confirmed by Reactome pathway annotation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-373713	ACCEPT	Summary: Correct localization annotation from Reactome pathway "DCC heterodimerizes with UNC-5:Netrin-1". NTN1 functions extracellularly where it binds receptors. Reason: Core localization confirmed by Reactome pathway annotation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-373716	ACCEPT	Summary: Correct localization annotation from Reactome pathway "DCC interacting NCK-1". NTN1 functions extracellularly as a secreted guidance cue. Reason: Core localization confirmed by Reactome pathway annotation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-373751	ACCEPT	Summary: Correct localization annotation from Reactome pathway "UNC-5 binds Netrin-1". NTN1 binds UNC5 receptors extracellularly for repulsive guidance. Reason: Core localization confirmed by Reactome pathway annotation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-374665	ACCEPT	Summary: Correct localization annotation from Reactome pathway "DCC interaction with SIAH1". NTN1 functions extracellularly. Reason: Core localization confirmed by Reactome pathway annotation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-374667	ACCEPT	Summary: Correct localization annotation from Reactome pathway "DCC interaction with SIAH2". NTN1 functions extracellularly. Reason: Core localization confirmed by Reactome pathway annotation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-374701	ACCEPT	Summary: Correct localization annotation from Reactome pathway "Phosphorylation of DCC by Fyn". NTN1 functions extracellularly to trigger this signaling. Reason: Core localization confirmed by Reactome pathway annotation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-418850	ACCEPT	Summary: Correct localization annotation from Reactome pathway "Activation of Cdc42". NTN1 functions extracellularly to trigger downstream Cdc42 signaling. Reason: Core localization confirmed by Reactome pathway annotation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-418856	ACCEPT	Summary: Correct localization annotation from Reactome pathway "Activation of Rac1". NTN1 functions extracellularly. Reason: Core localization confirmed by Reactome pathway annotation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-418858	ACCEPT	Summary: Correct localization annotation from Reactome pathway "RhoGTPase GEF's recruited to DCC". NTN1 functions extracellularly. Reason: Core localization confirmed by Reactome pathway annotation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-418868	ACCEPT	Summary: Correct localization annotation from Reactome pathway "Recruitment of Src and Fyn to DCC:FADK1". NTN1 functions extracellularly. Reason: Core localization confirmed by Reactome pathway annotation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-418874	ACCEPT	Summary: Correct localization annotation from Reactome pathway "Recruitment and activation of N-WASP by Cdc42". NTN1 functions extracellularly. Reason: Core localization confirmed by Reactome pathway annotation.
GO:0005515 protein binding	IPI PMID:19196994 DSCAM functions as a netrin receptor in commissural axon pat...	MODIFY	Summary: Generic protein binding annotation based on interaction with DSCAM receptor. PMID:19196994 identifies DSCAM as a netrin receptor in commissural axon pathfinding. Reason: While the protein-protein interaction with DSCAM is valid and functionally important, "protein binding" is uninformative. Receptor binding would be more appropriate. Proposed replacements: netrin receptor binding Supporting Evidence: PMID:19196994 DSCAM functions as a netrin receptor in commissural axon pathfinding. file:human/NTN1/NTN1-deep-research-falcon.md Primary molecular function: Netrin-1 is a secreted extracellular matrix-associated ligand that signals through dependence receptors including DCC, NEO1, and UNC5-family members.
GO:0005515 protein binding	IPI PMID:10102268 Slit proteins bind Robo receptors and have an evolutionarily...	REMOVE	Summary: The generic protein-binding term is uninformative; the source experiment has not been excluded. Reason: The cached PMID:10102268 is abstract-only. Its focus on Slit/Robo does not establish that Netrin-1 was not also assayed, so the previous confident reference-misassignment claim is withdrawn. Removal follows the generic protein-binding convention, independently of the unresolved experimental details.

Gene Description

Existing Annotations Review

Core Functions

NTN1 functions as a secreted axon guidance cue that binds to netrin receptors including DCC (for attraction) and UNC5 family members (for repulsion). This receptor binding is the primary molecular function of the protein.

References

Deep Research

Falcon

📚 Additional Documentation

Notes

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