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: Erroneous IBA propagation from PANTHER:PTN000180816. NTN1 is a secreted axon guidance protein with no DNA-binding domains. See file:interpro/panther/PTHR10574/PTHR10574-review.md for detailed family analysis. Reason: NTN1 belongs to PTHR10574 (Netrin/Laminin family), not PTHR11636 (POU domain TFs). Erroneous phylogenetic grouping with POU-domain transcription factors. Supporting Evidence: file:interpro/panther/PTHR10574/PTHR10574-review.md CRITICAL ANNOTATION ERROR section documents erroneous IBA from PTN000180816
GO:0006357 regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	REMOVE	Summary: Erroneous IBA propagation - same root cause as GO:0000981. See family review. Reason: NTN1 is a secreted extracellular protein, not a transcription regulator. Supporting Evidence: file:interpro/panther/PTHR10574/PTHR10574-review.md See CRITICAL ANNOTATION ERROR section
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA GO_REF:0000033	REMOVE	Summary: Erroneous IBA propagation - same root cause as GO:0000981. See family review. Reason: NTN1 has no DNA-binding domains (laminin/EGF/NTR domains only). Supporting Evidence: file:interpro/panther/PTHR10574/PTHR10574-review.md See CRITICAL ANNOTATION ERROR section
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...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation. The reference identifies Draxin as a secreted netrin-1 antagonist, suggesting protein-protein interaction between NTN1 and Draxin. Reason: While the protein-protein interaction with Draxin is valid, "protein binding" is uninformative. This interaction represents an antagonistic relationship in axon guidance.
GO:0005515 protein binding	IPI PMID:28501620 Molecular characterization of Netrin-1 and APP receptor bind...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation based on interaction with APP (amyloid precursor protein). The reference characterizes netrin-1 and APP receptor binding. Reason: While the protein-protein interaction with APP is valid, "protein binding" is uninformative. The specific binding to APP receptor would be more informative.
GO:0005604 basement membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Acceptable localization based on ortholog transfer from mouse. Netrins are known to associate with extracellular matrix structures including basement membranes where they function as guidance cues. Reason: Secondary localization. Netrin-1 can associate with basement membrane as part of its extracellular guidance function, but the primary localization is extracellular region.
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: Generic protein binding annotation. The reference "Slit proteins bind Robo receptors" is about Slit proteins, not Netrin-1. The annotation may be based on interaction with shared pathway components. Reason: The cited reference is about Slit-Robo interactions, not Netrin-1, and does not support a NTN1 protein-binding annotation. This appears to be a clear reference misassignment rather than an inaccessible-publication case.

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.

Molecular Function:

netrin receptor binding

Directly Involved In:

chemorepulsion of axon positive regulation of axon extension

Cellular Locations:

extracellular region

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.
file:human/NTN1/NTN1-deep-research-falcon.md
Primary molecular function: Netrin-1 is a secreted extracellular matrix-associated ligand that provides positional/microenvironmental information through dependence receptors including DCC, NEO1, and UNC5-family members.

References

file:interpro/panther/PTHR10574/PTHR10574-review.md

PANTHER Family Review - Laminin/Netrin Extracellular Matrix (PTHR10574)

NTN1/NTN3 have erroneous IBA annotations from PANTHER node PTN000180816 which incorrectly grouped netrins with POU-domain TFs
PTHR10574 proteins are secreted ECM/guidance proteins with no DNA-binding domains

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:0000044

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

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

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

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10102268

Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance.

PMID:19196994

DSCAM functions as a netrin receptor in commissural axon pathfinding.

PMID:19721007

Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal cancer progression.

PMID:20434207

Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation.

PMID:26190107

A Floor-Plate Extracellular Protein-Protein Interaction Screen Identifies Draxin as a Secreted Netrin-1 Antagonist.

PMID:28501620

Molecular characterization of Netrin-1 and APP receptor binding: New leads to block the progression of senile plaques in Alzheimer's disease.

PMID:28945198

Mutations in the netrin-1 gene cause congenital mirror movements.

Reactome:R-HSA-373707

Netrin-1 induced DCC clustering

Reactome:R-HSA-373711

DCC interaction with Netrin-1

Reactome:R-HSA-373713

DCC heterodimerizes with UNC-5:Netrin-1

Reactome:R-HSA-373716

DCC interacting NCK-1

Reactome:R-HSA-373751

UNC-5 binds Netrin-1

Reactome:R-HSA-374665

DCC interaction with SIAH1

Reactome:R-HSA-374667

DCC interaction with SIAH2

Reactome:R-HSA-374701

Phosphorylation of DCC by Fyn

Reactome:R-HSA-418850

Activation of Cdc42

Reactome:R-HSA-418856

Activation of Rac1

Reactome:R-HSA-418858

RhoGTPase GEF's recruited to DCC

Reactome:R-HSA-418868

Recruitment of Src and Fyn to DCC:FADK1

Reactome:R-HSA-418874

Recruitment and activation of N-WASP by Cdc42

file:human/NTN1/NTN1-deep-research-falcon.md

Falcon deep research report for human NTN1

NTN1 encodes secreted Netrin-1, an extracellular matrix-associated ligand that signals through DCC, NEO1, UNC5-family receptors, and context-specific integrins.
The report supports Netrin-1 extracellular localization through secretion, ECM association, HSPG-dependent cell-surface organization, and receptor engagement in the extracellular microenvironment.

Deep Research

Falcon

(NTN1-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 34 citations 2026-05-10T22:15:28.730450

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.

Comprehensive research report: Human NTN1 (Netrin-1) functional annotation (UniProt O95631)

1) Target verification (identity, organism, domains)

The research target is human NTN1, encoding Netrin-1, a secreted laminin-related extracellular guidance cue (Homo sapiens). Independent recent sources consistently describe Netrin-1 as a multi-domain secreted protein with an N-terminal laminin-like (LN; “domain VI”) region, a central region with three laminin-type EGF-like repeats (LE1–LE3; “domain V”), and a C-terminal netrin-like (NTR) module, consistent with UniProt O95631 domain annotations (Laminin_N, LE domains, Laminin/Netrin ECM) (wu2025theroleof pages 4-6, cai2024insightsfromthe pages 2-3, gao2025pancanceranalysisreveals pages 1-3).

2) Key concepts and current understanding (definitions and mechanistic framework)

2.1 Netrin-1 as an extracellular morphogen/ECM cue

Netrin-1 was originally characterized as an axon guidance factor; contemporary literature emphasizes that it is a secreted extracellular cue that can diffuse through extracellular matrix (ECM) and form functional gradients (meier2023thedynamicnature pages 1-2). Beyond neurodevelopment, NTN1 is now broadly implicated in cell migration, adhesion, differentiation, survival, inflammation, angiogenesis/barrier biology, and cancer (meier2023thedynamicnature pages 1-2, cai2024insightsfromthe pages 1-2).

2.2 Canonical receptor logic: “dependence receptors”

A central concept for NTN1 biology is the dependence receptor paradigm, in which receptors (classically DCC and UNC5 family members) mediate different outcomes depending on ligand occupancy. In this framework, NTN1 binding promotes survival/migration/guidance signaling, whereas lack of ligand can favor pro-apoptotic receptor signaling (meier2023thedynamicnature pages 1-2, gao2025pancanceranalysisreveals pages 1-3). This paradigm is a major translational rationale for therapeutically blocking NTN1–receptor interactions in NTN1-dependent tumors (NCT02977195 chunk 1).

2.3 Major receptors and pathway outputs (current consensus)

Multiple authoritative sources enumerate NTN1 receptors, including DCC, UNC5A–D, neogenin (NEO1), and additional partners such as integrins and heparan sulfate proteoglycans (HSPGs) (wu2025theroleof pages 4-6, yu2024netrin1isan pages 1-3, gao2025pancanceranalysisreveals pages 1-3). Mechanistically, receptor context can switch response from attraction (e.g., DCC-centric signaling) to repulsion (UNC5-centric or UNC5/DCC combinations), and can engage second-messenger signaling (e.g., cAMP/Ca2+/cGMP in guidance contexts) (cai2024insightsfromthe pages 1-2, wu2025theroleof pages 4-6).

3) Protein localization, structural determinants, and processing (evidence-based)

3.1 Where NTN1 acts: secreted, ECM, and cell-surface–proximal organization

High-quality primary evidence supports that Netrin-1 is secreted and ECM-localized, and that it can be retained/organized at the cell surface via HSPGs. In a 2023 Nature Communications study, Netrin-1 (studied as NET1ΔC) formed cell-surface deposits and showed HSPG-dependent localization; heparan sulfate proteoglycans were described as platforms that co-localize Netrin-1 near the membrane (meier2023thedynamicnature pages 1-2, meier2023thedynamicnature pages 3-4).

Visual evidence (Figure-based): immune-gold EM and quantitative analyses show that addition of short heparin/heparan-oligosaccharides (HO-dp10) or heparanase expression changes NET1ΔC surface distribution, consistent with HSPG-dependent localization and ligand clustering (meier2023thedynamicnature media c5061845).

3.2 GAG/HSPG binding as a mechanism for ligand clustering and receptor presentation (2023 structural advance)

A key 2023 mechanistic advance is that short heparin/heparan-sulfate oligosaccharides (including fragments generated by heparanase cleavage) can profoundly alter NTN1 supramolecular behavior: they can abolish monomer–dimer equilibrium and promote hierarchical super-assemblies/filaments, while preserving dependence receptor binding (DCC/NEO1/UNC5B) (meier2023thedynamicnature pages 1-2, meier2023thedynamicnature pages 3-4).

Structurally, crystallography/mutagenesis mapped a major GAG-binding epitope to the LE-2 laminin-type EGF-like subdomain, which is electropositive and enriched in basic motifs; this provides a domain-resolved basis for how ECM glycans organize ligand distribution and potentially tune receptor engagement (meier2023thedynamicnature pages 3-4).

3.3 Domain contributions and secretion competency

Recent reviews reinforce that receptor binding is primarily supported by N-terminal LN and central LE regions, while the C-terminal NTR module is described as not strictly required for receptor binding but may modulate affinity and other extracellular interactions; importantly, mutations in the protein can impair secretion (i.e., failure to be secreted), consistent with a precursor/secreted protein lifecycle (wu2025theroleof pages 4-6, cai2024insightsfromthe pages 2-3).

4) Functional roles and pathways (with emphasis on 2023–2024 evidence)

4.1 Nervous system: guidance, microglial migration, and regenerative niches

Microglia migration (2024): A 2024 study demonstrated that extracellular Netrin-1 promotes microglial (BV2) migration and morphological elongation, with strong statistical support (elongation p = 0.0001; migration p < 0.0001). Mechanistically, the effect required GSK3β activity and was linked to integrin α6/β1 as a relevant receptor in microglia (single-cell expression enrichment; MST binding), highlighting non-canonical receptor usage in a defined cellular context (yu2024netrin1isan pages 1-3).

Peripheral nerve repair niche (2024): In peripheral nerve injury, NTN1 was reported upregulated after injury and associated with NTN1-high endothelial cells and endothelial exosomes that contribute to a pro-regenerative vascular niche. Multi-omics analyses implicated activation of pathways including focal adhesion, axon guidance, PI3K–AKT, and mTOR in this niche program (huang2024netrin1–engineeredendothelialcell pages 1-2).

4.2 Vascular biology: barrier integrity via UNC5B and β-catenin crosstalk (2024)

A 2024 PNAS study linked Netrin-1 signaling to endothelial barrier specialization in the retina. Using scRNA-seq, the authors identified >100 blood–retina barrier genes and reported that Netrin-1/Unc5b signaling contributes to arteriovenous zonation of barrier integrity; Ntn1 or Unc5b deficiency increased arterial-side barrier leakage and reduced β-catenin signaling and barrier gene expression, which could be rescued by β-catenin overactivation. Mechanistically, Netrin-1 and Norrin additively enhanced β-catenin transcriptional activity and Lrp5 phosphorylation via the Dlg1 scaffolding protein (furtado2024interplaybetweennetrin1 pages 1-2).

4.3 Inflammation and cardiometabolic disease contexts

Macrophage survival signaling (human cells; 2023): In inflammatory macrophages, the human long intergenic noncoding RNA SIMALR was shown to regulate NTN1 transcription (likely involving HIF1α), and NTN1 functioned as a macrophage survival factor: NTN1 knockdown induced apoptosis, while adding recombinant NTN1 rescued apoptosis induced by SIMALR knockdown. SIMALR expression was also detected in macrophages in symptomatic human carotid plaques, linking NTN1 regulation to human atherosclerosis biology (cynn2023humanmacrophagelong pages 1-3).

4.4 Cancer: survival, dormancy, EMT, and context-dependent anti-/pro-tumor functions

Dormancy survival via low-level ERK (2024 eLife): In high-grade serous ovarian cancer dormancy models, Netrin signaling was identified as a survival dependency. The study reported that Netrin-1/-3 and receptors were required for low-level ERK activation sufficient for survival without inducing proliferation, and that deleting UNC5-family receptors blocked Netrin signaling and reduced viability during dissemination in xenograft assays (perampalam2024netrinsignalingmediates pages 1-2).

YAP-driven cytostasis axis (2024): In a distinct cancer context (“YAPoff” cancers), CRISPR screens and functional assays identified an NTN1/UNC5B axis that cooperates with integrin-αV/β5 to mediate YAP-induced cytostasis, supporting that NTN1 signaling can be anti-proliferative in specific molecular contexts rather than universally pro-tumorigenic (pearson2024netrin1andunc5b pages 1-2).

Obesity–colon cancer crosstalk (human cohort; 2023): In a human cohort study of visceral adipose tissue, NTN1 and receptor expression changes linked obesity and colon cancer. The study reported increased VAT NTN1 and NEO1 mRNA associated with obesity (p < 0.05) and colon cancer (p < 0.001), plus increased DCC (p < 0.01) and UNC5B (p < 0.05) in colon cancer; in vitro, adipocyte-conditioned media and recombinant NTN-1 promoted colorectal cancer cell migration (mentxaka2023increasedexpressionlevels pages 1-2).

5) Recent developments (prioritizing 2023–2024)

The most notable 2023–2024 advances in NTN1 functional understanding from the retrieved literature include:
1. GAG fragment–driven filament/super-assembly mechanism and LE-2 GAG-binding epitope mapping that links ECM glycan remodeling (e.g., heparanase activity) to ligand clustering and potentially altered receptor presentation (Mar 2023) (meier2023thedynamicnature pages 3-4, meier2023thedynamicnature pages 1-2, meier2023thedynamicnature media c5061845).
2. Non-canonical integrin α6β1–GSK3β axis for microglial migration, supported by quantitative migration assays and direct binding measurements (Jun 2024) (yu2024netrin1isan pages 1-3).
3. Endothelial barrier program coupling UNC5B to β-catenin signaling in the blood–retina barrier, with scRNA-seq and genetic perturbation/rescue evidence (Dec 2024) (furtado2024interplaybetweennetrin1 pages 1-2).
4. Cancer dormancy survival mechanism: Netrin ligands/receptors sustaining survival via low-level ERK without driving proliferation (Jul 2024) (perampalam2024netrinsignalingmediates pages 1-2).

6) Current applications and real-world implementations

6.1 Therapeutic targeting: NP137 (anti-Netrin-1 monoclonal antibody)

Clinical translation targeting Netrin-1 is active, based explicitly on the dependence receptor paradigm.

First-in-human monotherapy (Phase I, completed): NCT02977195 tested NP137 (anti-Netrin-1 humanized mAb) in advanced/metastatic solid tumors; enrolled 70 participants; started 2017-01-09, completed 2022-06. The record states preclinical rationale that blocking Netrin-1 interaction with its receptors is sufficient to trigger death of Netrin-1–expressing tumor cells and inhibit tumor growth/metastasis, and it included biomarker cohorts using tumor biopsies and RNA-seq EMT profiling (NCT02977195 chunk 1).
Combination therapy in gynecologic cancers (Phase I/II, active-not-recruiting): NCT04652076 evaluates NP137 combined with carboplatin/paclitaxel and/or pembrolizumab in endometrial/cervix carcinoma; estimated enrollment 240; start 2020-12-14; last update posted 2024-10-08 (NCT04652076 chunk 1).
Add-on to PD-1/PD-L1 blockade (Phase II, active-not-recruiting): NCT05605496 evaluates NP137 (14 mg/kg IV Q3W) as add-on therapy in advanced/metastatic solid tumors receiving standard PD-1/PD-L1 blockade; actual enrollment 57; start 2023-01-06; last update posted 2026-04-24 (NCT05605496 chunk 1).

6.2 Biomarker implementation: hepatocellular carcinoma (HCC) observational cohort

NCT04766736 (“HCC-Net”) is an observational retrospective study (estimated N=320, start 2019-07-01) aiming to quantify Netrin-1 expression in HCC and matched non-tumor tissues, using immunoblotting and IHC with positivity thresholds. The record frames Netrin-1 as upregulated in chronic liver disease/cirrhosis/HCC and aims to define patient groups most likely to benefit from capturing/targeting Netrin-1 in preclinical models (NCT04766736 chunk 1).

6.3 Human genetic/disease associations (curated)

OpenTargets disease–target evidence links NTN1 to developmental disorders including cleft lip, cleft palate, and orofacial cleft, and to familial congenital mirror movements/mirror movements 4, consistent with the central role of NTN1 guidance signaling in development (OpenTargets Search: -NTN1).

7) Statistics and data highlights from recent studies

Microglia migration: Netrin-1 increased microglial elongation (p = 0.0001) and transwell migration (p < 0.0001), with mechanistic dependence on GSK3β and evidence for integrin α6/β1 receptor involvement (Jun 2024) (yu2024netrin1isan pages 1-3).
HSPG/NET1 surface distribution: NET1ΔC surface localization differences under HO-dp10/heparanase conditions were significant (ordinary one-way ANOVA, Tukey correction, ****P < 0.0001), and multiple assays used N=3 technical repeats (Mar 2023) (meier2023thedynamicnature pages 3-4, meier2023thedynamicnature media c5061845).
Human obesity/colon cancer cohort: Visceral adipose tissue analysis included 74 normal-weight participants and 49 with obesity; VAT NTN1/NEO1 increased with obesity (p < 0.05) and colon cancer (p < 0.001), and DCC/UNC5B were upregulated in colon cancer (Feb 2023) (mentxaka2023increasedexpressionlevels pages 1-2).
Clinical trials (NP137): enrollment and timelines include N=70 (NCT02977195), N=240 est. (NCT04652076), and N=57 actual (NCT05605496) (NCT02977195 chunk 1, NCT04652076 chunk 1, NCT05605496 chunk 1).

8) Expert opinions / authoritative synthesis (2024 review perspective)

A 2024 review emphasized Netrin-1’s evolution from a neurodevelopmental guidance cue to a multisystem regulator implicated in inflammation, tumorigenesis, and neurodegeneration, noting broad tissue distribution and multi-receptor signaling (DCC/UNC5 as core, with additional receptors proposed in a context-dependent manner) (cai2024insightsfromthe pages 1-2). The review also highlights clinical translational interest in blocking Netrin-1 and the feasibility of measuring Netrin-1 in biofluids, supporting biomarker and therapeutic strategies (cai2024insightsfromthe pages 6-7).

9) Summary for functional annotation (NTN1 / Netrin-1)

Primary molecular function (mechanistic): Netrin-1 is a secreted extracellular matrix-associated ligand that provides positional/microenvironmental information and survival/motility regulation through dependence receptors (DCC/NEO1/UNC5 family) and, in specific contexts, integrins (meier2023thedynamicnature pages 1-2, wu2025theroleof pages 4-6, yu2024netrin1isan pages 1-3).

Primary biological processes (supported by evidence):
- Guidance and migration programs in nervous and immune cells (yu2024netrin1isan pages 1-3, cai2024insightsfromthe pages 1-2).
- Vascular niche formation and regeneration-associated signaling (focal adhesion/PI3K–AKT/mTOR) (huang2024netrin1–engineeredendothelialcell pages 1-2).
- Endothelial barrier integrity via UNC5B crosstalk with β-catenin/Lrp5-Dlg1 signaling (furtado2024interplaybetweennetrin1 pages 1-2).
- Survival signaling in inflammatory macrophages and dormant cancer cells (cynn2023humanmacrophagelong pages 1-3, perampalam2024netrinsignalingmediates pages 1-2).

Cellular/extracellular location: Predominantly secreted/extracellular, operating in the ECM and at the cell surface microenvironment via HSPG glycan binding and higher-order assembly, enabling receptor engagement in a spatially controlled manner (meier2023thedynamicnature pages 1-2, meier2023thedynamicnature pages 3-4, meier2023thedynamicnature media c5061845).

Recent 2023–2024 evidence map (key studies)

Study	Publication/date + URL/DOI	System/model	Key mechanistic finding (pathway/receptor)	Quantitative/statistical highlights	Relevance to functional annotation
Meier 2023	Nature Communications (Mar 2023) https://doi.org/10.1038/s41467-023-36692-w	Structural/biophysical study of NTN1/NET1ΔC with HEK-293 cells, glypican-3, dependence receptor ectodomains, heparin/heparan-sulfate oligosaccharides	Human Netrin-1 is a secreted laminin-related cue whose major GAG-binding epitope maps to the LE-2 subdomain; HSPGs localize NTN1 near the cell surface, and short heparan-sulfate/heparin fragments abolish the monomer-dimer equilibrium and drive filament/super-assembly formation while preserving dependence-receptor binding (DCC, NEO1, UNC5B) (meier2023thedynamicnature pages 1-2, meier2023thedynamicnature pages 3-4, meier2023thedynamicnature media c5061845)	NET1ΔC bound HSPGs with nM-range affinities; gold-particle density on HEK-293 surfaces differed significantly by ordinary one-way ANOVA with Tukey correction, ****P < 0.0001; multiple assays used N = 3 technical repeats (meier2023thedynamicnature pages 1-2, meier2023thedynamicnature pages 3-4)	Strong evidence that NTN1 functions extracellularly in ECM/glycocalyx context; supports UniProt domain architecture (LN/LE/NTR) and explains how localization on HSPGs can modulate receptor engagement and guidance signaling (meier2023thedynamicnature pages 1-2, meier2023thedynamicnature pages 3-4)
Yu 2024	International Journal of Molecular Sciences (Jun 2024) https://doi.org/10.3390/ijms25137079	BV2 microglia migration assays, single-cell analysis, MST binding, conditional mouse knockout	Extracellular Netrin-1 promotes microglial migration through integrin α6/β1 rather than classical DCC/UNC5 receptors in this context, with GSK3β activation required downstream; radial-glia-derived Netrin-1 contributes to early cortical microglia colonization (yu2024netrin1isan pages 1-3)	BV2 elongation p = 0.0001; transwell migration p < 0.0001; MST confirmed high-affinity Netrin-1–integrin α6/β1 binding; cortical microglia reduced in conditional knockout at early stages, then normalized by P14 (yu2024netrin1isan pages 1-3)	Demonstrates receptor/context specificity of NTN1 function beyond canonical dependence receptors; annotates NTN1 as a secreted motility-regulating cue in CNS immune cell migration (yu2024netrin1isan pages 1-3)
Furtado 2024	PNAS (Dec 18 2024) https://doi.org/10.1073/pnas.2408674121	Mouse retinal endothelial cells, scRNA-seq, Ntn1 and Unc5b mutants, β-catenin rescue experiments	Netrin-1/Unc5b signaling establishes arterial-side blood-retina barrier integrity and cooperates additively with Norrin/Lrp5 signaling to enhance β-catenin transcriptional activity and Lrp5 phosphorylation via Dlg1; endothelial Lrp5-Unc5b pathways converge in capillary BRB protection (furtado2024interplaybetweennetrin1 pages 1-2)	scRNA-seq identified >100 BRB genes; Ntn1- or Unc5b-deficient mice showed increased arterial BRB leakage, and β-catenin overactivation rescued downregulated BRB gene expression/integrity phenotypes (furtado2024interplaybetweennetrin1 pages 1-2)	Clarifies a vascular/barrier role for secreted NTN1 acting on UNC5B in endothelium; functionally annotates NTN1 in endothelial barrier maintenance and β-catenin pathway modulation (furtado2024interplaybetweennetrin1 pages 1-2)
Huang 2024	Science Advances (Jun 28 2024) https://doi.org/10.1126/sciadv.adm8454	Peripheral nerve injury, scRNA-seq, NTN1-high endothelial cells, endothelial exosomes, HUVEC overexpression system	NTN1-high endothelial cells are a vascular-niche component promoting angiogenesis, axon regeneration, and repair phenotypes; NTN1-engineered endothelial exosomes help build a pre-regenerative niche and activate focal adhesion, axon guidance, PI3K-AKT, and mTOR pathways (huang2024netrin1–engineeredendothelialcell pages 1-2)	Multi-omics implicated low let7a-5p cargo in NTN1 EC-EXO; pathway activation included focal adhesion, axon guidance, PI3K-AKT, and mTOR signaling (huang2024netrin1–engineeredendothelialcell pages 1-2)	Supports annotation of NTN1 as a secreted microenvironmental organizer acting outside cells in nerve repair, vascular niche formation, and angiogenesis-linked regenerative signaling (huang2024netrin1–engineeredendothelialcell pages 1-2)
Pearson 2024	Cancer Research Communications (Sep 2024) https://doi.org/10.1158/2767-9764.CRC-24-0101	YAPoff cancers (including retinoblastoma/SCLC contexts), CRISPR screens, knockout and peptide/decoy receptor assays	Netrin-1 and UNC5B cooperate with integrin-αV/β5 to mediate YAP-driven cytostasis, revealing a tumor-suppressive NTN1/UNC5B/integrin axis in YAPoff cancers rather than a purely pro-tumor role (pearson2024netrin1andunc5b pages 1-2)	Mechanism built from CRISPR screening and functional knockout/blocking assays; no explicit cohort N reported in provided context (pearson2024netrin1andunc5b pages 1-2)	Important for functional annotation because NTN1 signaling is bidirectional/context-dependent: same ligand can support survival in some settings yet mediate cytostasis with UNC5B/integrin signaling in others (pearson2024netrin1andunc5b pages 1-2)
Perampalam 2024	eLife (Version of record Jul 18 2024) https://doi.org/10.7554/eLife.91766.3	Dormant high-grade serous ovarian cancer spheroids, CRISPR screens, RNA-seq, xenograft dissemination assays	Netrin signaling is a survival dependency in dormant ovarian cancer cells; Netrin-1/-3 and UNC5 receptors maintain low-level ERK signaling sufficient for survival without inducing proliferation, and UNC5-family deletion blocks signaling and compromises viability during dissemination (perampalam2024netrinsignalingmediates pages 1-2)	Study used a novel CRISPR screening approach plus RNA-seq; overexpression of Netrin-1/-3 correlated with poor outcome; xenograft assays showed increased dissemination when Netrin signaling was active (perampalam2024netrinsignalingmediates pages 1-2)	Refines annotation of NTN1 as a survival ligand acting through dependence receptors and low-level ERK signaling, especially in metastatic dormancy contexts (perampalam2024netrinsignalingmediates pages 1-2)
Mentxaka 2023	Cancers (Feb 7 2023) https://doi.org/10.3390/cancers15041038	Human visceral adipose tissue from 74 NW and 49 obese patients, colon cancer subsets; colorectal cell lines; rat caloric restriction model	NTN1 is upregulated in obese and colon-cancer-associated visceral adipose tissue and promotes a pro-migratory microenvironment for colorectal cancer cells; implicated receptors include NEO1, DCC, and UNC5B (mentxaka2023increasedexpressionlevels pages 1-2)	Human cohort: 74 total NW-group participants and 49 with obesity; VAT NTN1 and NEO1 increased with obesity (p < 0.05) and colon cancer (p < 0.001); DCC increased (p < 0.01), UNC5B increased (p < 0.05); caloric restriction decreased colonic Ntn1 (p < 0.01); ACM/NTN-1 altered receptor mRNAs and increased migration (mentxaka2023increasedexpressionlevels pages 1-2)	Demonstrates extracellular/adipose-source NTN1 as an inflammation- and migration-linked cue in obesity/cancer crosstalk; useful for annotating tissue-context expression and receptor-associated migratory effects (mentxaka2023increasedexpressionlevels pages 1-2)
Cynn 2023	Arteriosclerosis, Thrombosis, and Vascular Biology (Feb 2023) https://doi.org/10.1161/ATVBAHA.122.318353	Human monocyte-derived macrophages, THP1 macrophages, promoter/reporter assays, human carotid plaque RNAscope	NTN1 acts as a macrophage survival factor in inflammatory macrophages; the lncRNA SIMALR promotes NTN1 transcription, likely with HIF1α, and recombinant NTN1 rescues apoptosis caused by SIMALR knockdown (cynn2023humanmacrophagelong pages 1-3)	SIMALR knockdown increased cleaved PARP, caspase-9, caspase-3, and Annexin V+ cells; NTN1 knockdown phenocopied apoptosis, and recombinant NTN1 rescued the effect; SIMALR detected in macrophages in symptomatic human carotid plaques (cynn2023humanmacrophagelong pages 1-3)	Strong evidence for NTN1 function in inflammatory-cell survival and atherosclerosis-related macrophage biology; annotates NTN1 as an extracellular survival cue regulated transcriptionally in human disease cells (cynn2023humanmacrophagelong pages 1-3)

Table: This table summarizes recent 2023–2024 mechanistic studies on human NTN1/Netrin-1 relevant to functional annotation, including receptor usage, pathways, extracellular localization, and disease-related functions. It highlights quantitative findings where available and links each study to specific annotation-relevant roles.

Translational/clinical landscape (trials + curated genetic links)

Program/type	Condition/indication	Trial ID or OpenTargets disease ID	Phase/design	Enrollment (N)	Key dates (start/completion/last update)	Key rationale/endpoint	URL
NP137 anti-Netrin-1 mAb	Advanced/metastatic solid tumors; expansion including HR+ endometrial carcinoma	NCT02977195	Phase I; open-label, single-group, dose-escalation + expansion	70	Start: 2017-01-09; Primary completion: 2021-12; Completion: 2022-06; Last update posted: 2022-07-25	First-in-human test of a humanized anti-Netrin-1 mAb based on the dependence-receptor paradigm; primary goals included DLT/MTD-RP2D, PK/PD, and 3-month ORR; biomarker cohorts used tumor biopsies and RNA-seq EMT profiling (NCT02977195 chunk 1)	https://clinicaltrials.gov/study/NCT02977195
NP137 anti-Netrin-1 mAb	Advanced/metastatic endometrial carcinoma or cervix carcinoma after prior systemic therapy	NCT04652076	Phase I/II; randomized, multicenter, open-label, parallel arms	240 (estimated)	Start: 2020-12-14; Primary completion: 2025-10-30 (est.); Completion: 2026-07-30 (est.); Last update posted: 2024-10-08	Tests NP137 with carboplatin/paclitaxel and/or pembrolizumab; rationale is restoration of apoptosis by blocking Netrin-1; endpoints include safety run-in DLTs and ORR, with PFS/OS and PK as secondary outcomes (NCT04652076 chunk 1)	https://clinicaltrials.gov/study/NCT04652076
NP137 anti-Netrin-1 mAb add-on immunotherapy	Advanced/metastatic solid tumors on standard anti-PD-1/PD-L1 therapy (stable disease, primary refractory, secondary refractory cohorts)	NCT05605496	Phase II; multicenter, open-label, proof-of-concept, non-randomized parallel cohorts	57	Start: 2023-01-06; Primary completion: 2027-01-01 (est.); Completion: 2027-01-01 (est.); Last update posted: 2026-04-24	Evaluates NP137 (14 mg/kg IV Q3W) added to PD-1/PD-L1 blockade; endpoints include ORR-12W or PFR-12W, safety, EMT-score changes on biopsies, and tumor microenvironment modulation (NCT05605496 chunk 1)	https://clinicaltrials.gov/study/NCT05605496
Biomarker observational study	Hepatocellular carcinoma (HCC)	NCT04766736	Observational, retrospective cohort	320 (estimated)	Start: 2019-07-01; Primary completion: 2021-06-30 (est.); Completion: 2022-12-31 (est.)	Characterizes Netrin-1 expression/signaling in HCC and adjacent tissues; rationale is that Netrin-1 is upregulated in chronic liver disease/cirrhosis/HCC; assays include immunoblotting and IHC to define positivity thresholds and stratify patients for potential Netrin-1 capture strategies (NCT04766736 chunk 1)	https://clinicaltrials.gov/study/NCT04766736
Genetic association	Cleft lip	EFO_0003959	OpenTargets disease-target association	—	OpenTargets query context retrieved in current session	Curated association of NTN1 with cleft lip; evidence count 5; association score 0.5286, relevant to developmental/craniofacial biology rather than therapeutic intervention (OpenTargets Search: -NTN1)	https://platform.opentargets.org/target/ENSG00000065320/associations
Genetic association	Orofacial cleft	MONDO_0000358	OpenTargets disease-target association	—	OpenTargets query context retrieved in current session	Curated association of NTN1 with orofacial cleft; evidence count 5; association score 0.5727 (OpenTargets Search: -NTN1)	https://platform.opentargets.org/target/ENSG00000065320/associations
Genetic association	Cleft palate	MONDO_0016064	OpenTargets disease-target association	—	OpenTargets query context retrieved in current session	Curated association of NTN1 with cleft palate; evidence count 5; association score 0.5321 (OpenTargets Search: -NTN1)	https://platform.opentargets.org/target/ENSG00000065320/associations
Genetic association	Familial congenital mirror movements	MONDO_0016558	OpenTargets disease-target association	—	OpenTargets query context retrieved in current session	Curated NTN1 association with familial congenital mirror movements; evidence count 5; association score 0.6853; DCC is also associated in the same disease, consistent with NTN1-DCC pathway involvement (OpenTargets Search: -NTN1)	https://platform.opentargets.org/target/ENSG00000065320/associations
Genetic association	Mirror movements 4	MONDO_0032641	OpenTargets disease-target association	—	OpenTargets query context retrieved in current session	Curated NTN1 association with mirror movements 4; evidence count 5; association score 0.6611 (OpenTargets Search: -NTN1)	https://platform.opentargets.org/target/ENSG00000065320/associations

Table: This table summarizes the main translational programs and disease associations for human NTN1/Netrin-1, including anti-Netrin-1 antibody trials, an HCC biomarker study, and curated OpenTargets genetic associations. It is useful for linking functional biology to current clinical development and human disease relevance.

References

(wu2025theroleof pages 4-6): Yi Wu, Zhiying Liu, Peiqi Xu, Kai Yin, and Shengjun Wang. The role of macrophage-derived netrin-1 in inflammatory diseases. Biomolecules, 15:921, Jun 2025. URL: https://doi.org/10.3390/biom15070921, doi:10.3390/biom15070921. This article has 5 citations.
(cai2024insightsfromthe pages 2-3): Minqi Cai, Qian Zheng, Yiqiang Chen, Siyuan Liu, Huimin Zhu, and Bing Bai. Insights from the neural guidance factor netrin-1 into neurodegeneration and other diseases. Frontiers in Molecular Neuroscience, Apr 2024. URL: https://doi.org/10.3389/fnmol.2024.1379726, doi:10.3389/fnmol.2024.1379726. This article has 16 citations.
(gao2025pancanceranalysisreveals pages 1-3): Ying Gao, Yuchen Hu, Yuyan Zhu, Xiaoli Gao, Wenjun Hao, Xi Chen, and Zhendong Zheng. Pan-cancer analysis reveals netrin-1 receptors as potential tumor biomarkers and immune-related therapeutic targets. Scientific Reports, Dec 2025. URL: https://doi.org/10.1038/s41598-025-28437-0, doi:10.1038/s41598-025-28437-0. This article has 2 citations and is from a peer-reviewed journal.
(meier2023thedynamicnature pages 1-2): Markus Meier, Monika Gupta, Serife Akgül, Matthew McDougall, Thomas Imhof, Denise Nikodemus, Raphael Reuten, Aniel Moya-Torres, Vu To, Fraser Ferens, Fabian Heide, Gay Pauline Padilla-Meier, Philipp Kukura, Wenming Huang, Birgit Gerisch, Matthias Mörgelin, Kate Poole, Adam Antebi, Manuel Koch, and Jörg Stetefeld. The dynamic nature of netrin-1 and the structural basis for glycosaminoglycan fragment-induced filament formation. Nature Communications, Mar 2023. URL: https://doi.org/10.1038/s41467-023-36692-w, doi:10.1038/s41467-023-36692-w. This article has 21 citations and is from a highest quality peer-reviewed journal.
(cai2024insightsfromthe pages 1-2): Minqi Cai, Qian Zheng, Yiqiang Chen, Siyuan Liu, Huimin Zhu, and Bing Bai. Insights from the neural guidance factor netrin-1 into neurodegeneration and other diseases. Frontiers in Molecular Neuroscience, Apr 2024. URL: https://doi.org/10.3389/fnmol.2024.1379726, doi:10.3389/fnmol.2024.1379726. This article has 16 citations.
(NCT02977195 chunk 1): First in Human Evaluation of Safety, Pharmacokinetics, and Clinical Activity of a Monoclonal Antibody Targeting Netrin 1 in Patients With Advanced/Metastatic Solid Tumors. Centre Leon Berard. 2017. ClinicalTrials.gov Identifier: NCT02977195
(yu2024netrin1isan pages 1-3): Hua-Li Yu, Xiu Liu, Yue Yin, Xiao-Nuo Liu, Yu-Yao Feng, Muhammad Mateen Tahir, Xin-Zhi Miao, Xiao-Xiao He, Zi-Xuan He, and Xiao-Juan Zhu. Netrin-1 is an important mediator in microglia migration. International Journal of Molecular Sciences, 25:7079, Jun 2024. URL: https://doi.org/10.3390/ijms25137079, doi:10.3390/ijms25137079. This article has 2 citations.
(meier2023thedynamicnature pages 3-4): Markus Meier, Monika Gupta, Serife Akgül, Matthew McDougall, Thomas Imhof, Denise Nikodemus, Raphael Reuten, Aniel Moya-Torres, Vu To, Fraser Ferens, Fabian Heide, Gay Pauline Padilla-Meier, Philipp Kukura, Wenming Huang, Birgit Gerisch, Matthias Mörgelin, Kate Poole, Adam Antebi, Manuel Koch, and Jörg Stetefeld. The dynamic nature of netrin-1 and the structural basis for glycosaminoglycan fragment-induced filament formation. Nature Communications, Mar 2023. URL: https://doi.org/10.1038/s41467-023-36692-w, doi:10.1038/s41467-023-36692-w. This article has 21 citations and is from a highest quality peer-reviewed journal.
(meier2023thedynamicnature media c5061845): Markus Meier, Monika Gupta, Serife Akgül, Matthew McDougall, Thomas Imhof, Denise Nikodemus, Raphael Reuten, Aniel Moya-Torres, Vu To, Fraser Ferens, Fabian Heide, Gay Pauline Padilla-Meier, Philipp Kukura, Wenming Huang, Birgit Gerisch, Matthias Mörgelin, Kate Poole, Adam Antebi, Manuel Koch, and Jörg Stetefeld. The dynamic nature of netrin-1 and the structural basis for glycosaminoglycan fragment-induced filament formation. Nature Communications, Mar 2023. URL: https://doi.org/10.1038/s41467-023-36692-w, doi:10.1038/s41467-023-36692-w. This article has 21 citations and is from a highest quality peer-reviewed journal.
(huang2024netrin1–engineeredendothelialcell pages 1-2): Jinsheng Huang, Jiangnan Li, Senrui Li, Xiaoqi Yang, Nianci Huo, Qiang Chen, Wengang Wang, Ningning Yang, Yuanyi Wang, and Nan Zhou. Netrin-1–engineered endothelial cell exosomes induce the formation of pre-regenerative niche to accelerate peripheral nerve repair. Science Advances, Jun 2024. URL: https://doi.org/10.1126/sciadv.adm8454, doi:10.1126/sciadv.adm8454. This article has 46 citations and is from a highest quality peer-reviewed journal.
(furtado2024interplaybetweennetrin1 pages 1-2): Jessica Furtado, Luiz Henrique Geraldo, Felipe Saceanu Leser, Bartlomiej Bartkowiak, Mathilde Poulet, Hyojin Park, Mark Robinson, Laurence Pibouin-Fragner, Anne Eichmann, and Kevin Boyé. Interplay between netrin-1 and norrin controls arteriovenous zonation of blood–retina barrier integrity. Proceedings of the National Academy of Sciences of the United States of America, Dec 2024. URL: https://doi.org/10.1073/pnas.2408674121, doi:10.1073/pnas.2408674121. This article has 7 citations and is from a highest quality peer-reviewed journal.
(cynn2023humanmacrophagelong pages 1-3): Esther Cynn, Daniel Y. Li, Marcella E. O’Reilly, Ying Wang, Alexander C. Bashore, Anjali Jha, Andrea S. Foulkes, Hanrui Zhang, Hanna Winter, Lars Maegdefessel, Hanying Yan, Mingyao Li, Leila Ross, Chenyi Xue, and Muredach P. Reilly. Human macrophage long intergenic noncoding rna, simalr , suppresses inflammatory macrophage apoptosis via ntn1 (netrin-1). Arteriosclerosis, Thrombosis, and Vascular Biology, 43:286-299, Feb 2023. URL: https://doi.org/10.1161/atvbaha.122.318353, doi:10.1161/atvbaha.122.318353. This article has 23 citations and is from a domain leading peer-reviewed journal.
(perampalam2024netrinsignalingmediates pages 1-2): Pirunthan Perampalam, James I MacDonald, Komila Zakirova, Daniel T Passos, Sumaiyah Wasif, Yudith Ramos-Valdes, Maeva Hervieu, Patrick Mehlen, Rob Rottapel, Benjamin Gibert, Rohann JM Correa, Trevor G Shepherd, and Frederick A Dick. Netrin signaling mediates survival of dormant epithelial ovarian cancer cells. eLife, Jul 2024. URL: https://doi.org/10.7554/elife.91766.3, doi:10.7554/elife.91766.3. This article has 11 citations and is from a domain leading peer-reviewed journal.
(pearson2024netrin1andunc5b pages 1-2): Joel D. Pearson, Katherine Huang, Louis G. Dela Pena, Benjamin Ducarouge, Patrick Mehlen, and Rod Bremner. Netrin-1 and unc5b cooperate with integrins to mediate yap-driven cytostasis. Cancer Research Communications, 4:2374-2383, Sep 2024. URL: https://doi.org/10.1158/2767-9764.crc-24-0101, doi:10.1158/2767-9764.crc-24-0101. This article has 2 citations and is from a peer-reviewed journal.
(mentxaka2023increasedexpressionlevels pages 1-2): Amaia Mentxaka, Javier Gómez-Ambrosi, Gabriela Neira, Beatriz Ramírez, Sara Becerril, Amaia Rodríguez, Víctor Valentí, Rafael Moncada, Jorge Baixauli, María A. Burrell, Camilo Silva, Vasco Claro, Albert Ferro, Victoria Catalán, and Gema Frühbeck. Increased expression levels of netrin-1 in visceral adipose tissue during obesity favour colon cancer cell migration. Cancers, 15:1038, Feb 2023. URL: https://doi.org/10.3390/cancers15041038, doi:10.3390/cancers15041038. This article has 7 citations.
(NCT04652076 chunk 1): GYNecological Cancers Treated with NETrin MAbs in Combination with Chemotherapy and /or Pembrolizumab. NETRIS Pharma. 2020. ClinicalTrials.gov Identifier: NCT04652076
(NCT05605496 chunk 1): NP137 Clinical and Biological Activities Assessment in Patients With Advanced/Metastatic Solid Tumors Treated by Standard Anti PD-1/PD-L1 Immunotherapies. Centre Leon Berard. 2023. ClinicalTrials.gov Identifier: NCT05605496
(NCT04766736 chunk 1): Netrin-1 & Hepatocellular Carcinoma HCC. Hospices Civils de Lyon. 2019. ClinicalTrials.gov Identifier: NCT04766736
(OpenTargets Search: -NTN1): Open Targets Query (-NTN1, 6 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(cai2024insightsfromthe pages 6-7): Minqi Cai, Qian Zheng, Yiqiang Chen, Siyuan Liu, Huimin Zhu, and Bing Bai. Insights from the neural guidance factor netrin-1 into neurodegeneration and other diseases. Frontiers in Molecular Neuroscience, Apr 2024. URL: https://doi.org/10.3389/fnmol.2024.1379726, doi:10.3389/fnmol.2024.1379726. This article has 16 citations.

Citations

meier2023thedynamicnature pages 1-2
meier2023thedynamicnature pages 3-4
cynn2023humanmacrophagelong pages 1-3
perampalam2024netrinsignalingmediates pages 1-2
mentxaka2023increasedexpressionlevels pages 1-2
cai2024insightsfromthe pages 1-2
cai2024insightsfromthe pages 6-7
wu2025theroleof pages 4-6
cai2024insightsfromthe pages 2-3
gao2025pancanceranalysisreveals pages 1-3
https://doi.org/10.1038/s41467-023-36692-w
https://doi.org/10.3390/ijms25137079
https://doi.org/10.1073/pnas.2408674121
https://doi.org/10.1126/sciadv.adm8454
https://doi.org/10.1158/2767-9764.CRC-24-0101
https://doi.org/10.7554/eLife.91766.3
https://doi.org/10.3390/cancers15041038
https://doi.org/10.1161/ATVBAHA.122.318353
https://clinicaltrials.gov/study/NCT02977195
https://clinicaltrials.gov/study/NCT04652076
https://clinicaltrials.gov/study/NCT05605496
https://clinicaltrials.gov/study/NCT04766736
https://platform.opentargets.org/target/ENSG00000065320/associations
https://doi.org/10.3390/biom15070921,
https://doi.org/10.3389/fnmol.2024.1379726,
https://doi.org/10.1038/s41598-025-28437-0,
https://doi.org/10.1038/s41467-023-36692-w,
https://doi.org/10.3390/ijms25137079,
https://doi.org/10.1126/sciadv.adm8454,
https://doi.org/10.1073/pnas.2408674121,
https://doi.org/10.1161/atvbaha.122.318353,
https://doi.org/10.7554/elife.91766.3,
https://doi.org/10.1158/2767-9764.crc-24-0101,
https://doi.org/10.3390/cancers15041038,

📄 View Raw YAML

id: O95631
gene_symbol: NTN1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Netrin-1 is a secreted laminin-related protein that functions as an axon guidance cue.
  It controls guidance of CNS commissural axons and peripheral motor axons through
  interactions with its receptors DCC and UNC5 family members. Binding to DCC leads to
  axon attraction, while binding to UNC5 receptors leads to axon repulsion. Netrin-1
  also serves as a survival factor that prevents initiation of apoptosis, and is involved
  in tumorigenesis through regulation of apoptosis. The protein contains a laminin N-terminal
  domain, three laminin EGF-like domains, and a C-terminal NTR domain. It is primarily secreted
  but can also be found in the cytoplasm. Mutations in NTN1 cause congenital mirror movements
  (MRMV4) through disruption of corticospinal tract development.
existing_annotations:
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Erroneous IBA propagation from PANTHER:PTN000180816. NTN1 is a secreted axon guidance
      protein with no DNA-binding domains. See file:interpro/panther/PTHR10574/PTHR10574-review.md
      for detailed family analysis.
    action: REMOVE
    reason: >-
      NTN1 belongs to PTHR10574 (Netrin/Laminin family), not PTHR11636 (POU domain TFs).
      Erroneous phylogenetic grouping with POU-domain transcription factors.
    supported_by:
      - reference_id: file:interpro/panther/PTHR10574/PTHR10574-review.md
        supporting_text: "CRITICAL ANNOTATION ERROR section documents erroneous IBA from PTN000180816"
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Erroneous IBA propagation - same root cause as GO:0000981. See family review.
    action: REMOVE
    reason: >-
      NTN1 is a secreted extracellular protein, not a transcription regulator.
    supported_by:
      - reference_id: file:interpro/panther/PTHR10574/PTHR10574-review.md
        supporting_text: "See CRITICAL ANNOTATION ERROR section"
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Erroneous IBA propagation - same root cause as GO:0000981. See family review.
    action: REMOVE
    reason: >-
      NTN1 has no DNA-binding domains (laminin/EGF/NTR domains only).
    supported_by:
      - reference_id: file:interpro/panther/PTHR10574/PTHR10574-review.md
        supporting_text: "See CRITICAL ANNOTATION ERROR section"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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.
    action: ACCEPT
    reason: >-
      Core localization for NTN1 function. Netrin-1 is primarily a secreted protein that
      functions in the extracellular space as a diffusible guidance cue.
    supported_by:
      - reference_id: PMID:28945198
        supporting_text: "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."
      - reference_id: UniProt:O95631
        supporting_text: "Note=Mainly secreted"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary localization. The protein is primarily secreted but can be detected in
      cytoplasm, especially for mutant variants that have defective secretion.
    supported_by:
      - reference_id: PMID:28945198
        supporting_text: "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."
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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.
    action: MODIFY
    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_replacement_terms:
      - id: GO:0043066
        label: negative regulation of apoptotic process
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19721007
  review:
    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.
    action: MODIFY
    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_replacement_terms:
      - id: GO:1990890
        label: netrin receptor binding
    supported_by:
      - reference_id: file:human/NTN1/NTN1-deep-research-falcon.md
        supporting_text: "NTN1 is summarized as a secreted extracellular ligand that signals through dependence receptors including DCC, NEO1, and UNC5-family receptors."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20434207
  review:
    summary: >-
      Generic protein binding annotation based on interaction with DCC receptor. The
      reference describes DCC-netrin interaction in context of translation regulation.
    action: MODIFY
    reason: >-
      While the protein-protein interaction is valid, "protein binding" is uninformative.
      The specific DCC receptor binding would be more appropriate.
    proposed_replacement_terms:
      - id: GO:1990890
        label: netrin receptor binding
    supported_by:
      - reference_id: file:human/NTN1/NTN1-deep-research-falcon.md
        supporting_text: "The report supports Netrin-1 receptor-ligand function through DCC, NEO1, and UNC5-family dependence receptors."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26190107
  review:
    summary: >-
      Generic protein binding annotation. The reference identifies Draxin as a secreted
      netrin-1 antagonist, suggesting protein-protein interaction between NTN1 and Draxin.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While the protein-protein interaction with Draxin is valid, "protein binding" is
      uninformative. This interaction represents an antagonistic relationship in axon guidance.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28501620
  review:
    summary: >-
      Generic protein binding annotation based on interaction with APP (amyloid precursor
      protein). The reference characterizes netrin-1 and APP receptor binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While the protein-protein interaction with APP is valid, "protein binding" is
      uninformative. The specific binding to APP receptor would be more informative.
- term:
    id: GO:0005604
    label: basement membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Acceptable localization based on ortholog transfer from mouse. Netrins are known
      to associate with extracellular matrix structures including basement membranes where
      they function as guidance cues.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary localization. Netrin-1 can associate with basement membrane as part of
      its extracellular guidance function, but the primary localization is extracellular region.
- term:
    id: GO:0045202
    label: synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Acceptable localization based on ortholog transfer. Netrin-1 plays roles in synapse
      formation and synaptic connectivity during neural development.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary localization relevant to NTN1's role in neural development and synapse
      assembly regulation.
- term:
    id: GO:0051963
    label: regulation of synapse assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Acceptable annotation based on ortholog transfer from mouse. Netrin-1 is known to
      regulate synapse formation during neural development through its guidance functions.
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream consequence of NTN1's axon guidance function. Synapse assembly is
      affected by proper axon pathfinding and target recognition.
- term:
    id: GO:0061643
    label: chemorepulsion of axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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."
    action: ACCEPT
    reason: >-
      Core function of NTN1. Axon chemorepulsion is mediated through UNC5 receptor
      binding and is essential for proper axon pathfinding.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary localization. While NTN1 may be present at glutamatergic synapses, this
      is a very specific localization that may require direct experimental validation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary localization. The protein is primarily secreted but can be detected in
      cytosol, consistent with transit through the secretory pathway.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:28945198
  review:
    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.
    action: ACCEPT
    reason: >-
      Core localization with strong experimental support. The secretion of NTN1 is essential
      for its function as an extracellular guidance cue.
    supported_by:
      - reference_id: PMID:28945198
        supporting_text: "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."
- term:
    id: GO:0061643
    label: chemorepulsion of axon
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      Core function annotation transferred from mouse ortholog. Axon chemorepulsion through
      UNC5 receptors is a well-established function of netrins conserved across species.
    action: ACCEPT
    reason: >-
      Core function of NTN1. Axon chemorepulsion is a conserved netrin function mediated
      through UNC5 receptor binding.
- term:
    id: GO:0006930
    label: substrate-dependent cell migration, cell extension
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      Acceptable annotation. Netrin-1 influences cell migration and extension through its
      guidance functions. This is downstream of receptor binding and signaling.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary biological process. Cell migration effects are downstream of NTN1's
      primary guidance function through receptor binding.
- term:
    id: GO:0007265
    label: Ras protein signal transduction
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream signaling consequence. NTN1 does not directly participate in Ras signaling
      but triggers it through receptor activation.
- term:
    id: GO:0032488
    label: Cdc42 protein signal transduction
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream signaling consequence. NTN1 triggers Cdc42 signaling through DCC receptor
      activation, leading to cytoskeletal changes for axon guidance.
- term:
    id: GO:0045773
    label: positive regulation of axon extension
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: ACCEPT
    reason: >-
      Core function of NTN1. Positive regulation of axon extension through DCC receptor
      is a fundamental netrin function in axon guidance.
- term:
    id: GO:2000147
    label: positive regulation of cell motility
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      Acceptable annotation. Netrin-1 promotes cell motility through its guidance functions.
      This is a broader consequence of its chemotactic activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary biological process. Cell motility regulation is downstream of NTN1's
      primary receptor-mediated guidance functions.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-373707
  review:
    summary: >-
      Correct localization annotation from Reactome pathway "Netrin-1 induced DCC clustering".
      NTN1 functions extracellularly where it binds DCC receptors.
    action: ACCEPT
    reason: >-
      Core localization. Extracellular region is the functional location for NTN1's
      role in receptor binding and axon guidance.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-373711
  review:
    summary: >-
      Correct localization annotation from Reactome pathway "DCC interaction with Netrin-1".
      NTN1 is secreted and functions extracellularly.
    action: ACCEPT
    reason: >-
      Core localization confirmed by Reactome pathway annotation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-373713
  review:
    summary: >-
      Correct localization annotation from Reactome pathway "DCC heterodimerizes with UNC-5:Netrin-1".
      NTN1 functions extracellularly where it binds receptors.
    action: ACCEPT
    reason: >-
      Core localization confirmed by Reactome pathway annotation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-373716
  review:
    summary: >-
      Correct localization annotation from Reactome pathway "DCC interacting NCK-1".
      NTN1 functions extracellularly as a secreted guidance cue.
    action: ACCEPT
    reason: >-
      Core localization confirmed by Reactome pathway annotation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-373751
  review:
    summary: >-
      Correct localization annotation from Reactome pathway "UNC-5 binds Netrin-1".
      NTN1 binds UNC5 receptors extracellularly for repulsive guidance.
    action: ACCEPT
    reason: >-
      Core localization confirmed by Reactome pathway annotation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-374665
  review:
    summary: >-
      Correct localization annotation from Reactome pathway "DCC interaction with SIAH1".
      NTN1 functions extracellularly.
    action: ACCEPT
    reason: >-
      Core localization confirmed by Reactome pathway annotation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-374667
  review:
    summary: >-
      Correct localization annotation from Reactome pathway "DCC interaction with SIAH2".
      NTN1 functions extracellularly.
    action: ACCEPT
    reason: >-
      Core localization confirmed by Reactome pathway annotation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-374701
  review:
    summary: >-
      Correct localization annotation from Reactome pathway "Phosphorylation of DCC by Fyn".
      NTN1 functions extracellularly to trigger this signaling.
    action: ACCEPT
    reason: >-
      Core localization confirmed by Reactome pathway annotation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-418850
  review:
    summary: >-
      Correct localization annotation from Reactome pathway "Activation of Cdc42".
      NTN1 functions extracellularly to trigger downstream Cdc42 signaling.
    action: ACCEPT
    reason: >-
      Core localization confirmed by Reactome pathway annotation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-418856
  review:
    summary: >-
      Correct localization annotation from Reactome pathway "Activation of Rac1".
      NTN1 functions extracellularly.
    action: ACCEPT
    reason: >-
      Core localization confirmed by Reactome pathway annotation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-418858
  review:
    summary: >-
      Correct localization annotation from Reactome pathway "RhoGTPase GEF's recruited to DCC".
      NTN1 functions extracellularly.
    action: ACCEPT
    reason: >-
      Core localization confirmed by Reactome pathway annotation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-418868
  review:
    summary: >-
      Correct localization annotation from Reactome pathway "Recruitment of Src and Fyn to DCC:FADK1".
      NTN1 functions extracellularly.
    action: ACCEPT
    reason: >-
      Core localization confirmed by Reactome pathway annotation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-418874
  review:
    summary: >-
      Correct localization annotation from Reactome pathway "Recruitment and activation of N-WASP by Cdc42".
      NTN1 functions extracellularly.
    action: ACCEPT
    reason: >-
      Core localization confirmed by Reactome pathway annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19196994
  review:
    summary: >-
      Generic protein binding annotation based on interaction with DSCAM receptor.
      PMID:19196994 identifies DSCAM as a netrin receptor in commissural axon pathfinding.
    action: MODIFY
    reason: >-
      While the protein-protein interaction with DSCAM is valid and functionally important,
      "protein binding" is uninformative. Receptor binding would be more appropriate.
    proposed_replacement_terms:
      - id: GO:1990890
        label: netrin receptor binding
    supported_by:
      - reference_id: PMID:19196994
        supporting_text: "DSCAM functions as a netrin receptor in commissural axon pathfinding."
      - reference_id: file:human/NTN1/NTN1-deep-research-falcon.md
        supporting_text: "Primary molecular function: Netrin-1 is a secreted extracellular matrix-associated ligand that signals through dependence receptors including DCC, NEO1, and UNC5-family members."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10102268
  review:
    summary: >-
      Generic protein binding annotation. The reference "Slit proteins bind Robo receptors"
      is about Slit proteins, not Netrin-1. The annotation may be based on interaction
      with shared pathway components.
    action: REMOVE
    reason: >-
      The cited reference is about Slit-Robo interactions, not Netrin-1, and does
      not support a NTN1 protein-binding annotation. This appears to be a clear
      reference misassignment rather than an inaccessible-publication case.
references:
- id: file:interpro/panther/PTHR10574/PTHR10574-review.md
  title: PANTHER Family Review - Laminin/Netrin Extracellular Matrix (PTHR10574)
  findings:
    - statement: NTN1/NTN3 have erroneous IBA annotations from PANTHER node PTN000180816 which incorrectly grouped netrins with POU-domain TFs
    - statement: PTHR10574 proteins are secreted ECM/guidance proteins with no DNA-binding domains
- 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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10102268
  title: Slit proteins bind Robo receptors and have an evolutionarily conserved role
    in repulsive axon guidance.
  findings: []
- id: PMID:19196994
  title: DSCAM functions as a netrin receptor in commissural axon pathfinding.
  findings: []
- id: PMID:19721007
  title: Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal
    cancer progression.
  findings: []
- id: PMID:20434207
  title: Transmembrane receptor DCC associates with protein synthesis machinery and
    regulates translation.
  findings: []
- id: PMID:26190107
  title: A Floor-Plate Extracellular Protein-Protein Interaction Screen Identifies
    Draxin as a Secreted Netrin-1 Antagonist.
  findings: []
- id: PMID:28501620
  title: 'Molecular characterization of Netrin-1 and APP receptor binding: New leads
    to block the progression of senile plaques in Alzheimer''s disease.'
  findings: []
- id: PMID:28945198
  title: Mutations in the netrin-1 gene cause congenital mirror movements.
  findings: []
- id: Reactome:R-HSA-373707
  title: Netrin-1 induced DCC clustering
  findings: []
- id: Reactome:R-HSA-373711
  title: DCC interaction with Netrin-1
  findings: []
- id: Reactome:R-HSA-373713
  title: DCC heterodimerizes with UNC-5:Netrin-1
  findings: []
- id: Reactome:R-HSA-373716
  title: DCC interacting NCK-1
  findings: []
- id: Reactome:R-HSA-373751
  title: UNC-5 binds Netrin-1
  findings: []
- id: Reactome:R-HSA-374665
  title: DCC interaction with SIAH1
  findings: []
- id: Reactome:R-HSA-374667
  title: DCC interaction with SIAH2
  findings: []
- id: Reactome:R-HSA-374701
  title: Phosphorylation of DCC by Fyn
  findings: []
- id: Reactome:R-HSA-418850
  title: Activation of Cdc42
  findings: []
- id: Reactome:R-HSA-418856
  title: Activation of Rac1
  findings: []
- id: Reactome:R-HSA-418858
  title: RhoGTPase GEF's recruited to DCC
  findings: []
- id: Reactome:R-HSA-418868
  title: Recruitment of Src and Fyn to DCC:FADK1
  findings: []
- id: Reactome:R-HSA-418874
  title: Recruitment and activation of N-WASP by Cdc42
  findings: []
- id: file:human/NTN1/NTN1-deep-research-falcon.md
  title: Falcon deep research report for human NTN1
  findings:
    - statement: NTN1 encodes secreted Netrin-1, an extracellular matrix-associated ligand that signals through DCC, NEO1, UNC5-family receptors, and context-specific integrins.
    - statement: The report supports Netrin-1 extracellular localization through secretion, ECM association, HSPG-dependent cell-surface organization, and receptor engagement in the extracellular microenvironment.
core_functions:
  - molecular_function:
      id: GO:1990890
      label: netrin receptor binding
    description: >-
      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.
    locations:
      - id: GO:0005576
        label: extracellular region
    directly_involved_in:
      - id: GO:0061643
        label: chemorepulsion of axon
      - id: GO:0045773
        label: positive regulation of axon extension
    supported_by:
      - reference_id: PMID:28945198
        supporting_text: "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."
      - reference_id: file:human/NTN1/NTN1-deep-research-falcon.md
        supporting_text: "Primary molecular function: Netrin-1 is a secreted extracellular matrix-associated ligand that provides positional/microenvironmental information through dependence receptors including DCC, NEO1, and UNC5-family members."

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

Comprehensive research report: Human NTN1 (Netrin-1) functional annotation (UniProt O95631)

1) Target verification (identity, organism, domains)

2) Key concepts and current understanding (definitions and mechanistic framework)

2.1 Netrin-1 as an extracellular morphogen/ECM cue

2.2 Canonical receptor logic: “dependence receptors”

2.3 Major receptors and pathway outputs (current consensus)

3) Protein localization, structural determinants, and processing (evidence-based)

3.1 Where NTN1 acts: secreted, ECM, and cell-surface–proximal organization

3.2 GAG/HSPG binding as a mechanism for ligand clustering and receptor presentation (2023 structural advance)

3.3 Domain contributions and secretion competency

4) Functional roles and pathways (with emphasis on 2023–2024 evidence)

4.1 Nervous system: guidance, microglial migration, and regenerative niches

4.2 Vascular biology: barrier integrity via UNC5B and β-catenin crosstalk (2024)

4.3 Inflammation and cardiometabolic disease contexts

4.4 Cancer: survival, dormancy, EMT, and context-dependent anti-/pro-tumor functions

5) Recent developments (prioritizing 2023–2024)

6) Current applications and real-world implementations

6.1 Therapeutic targeting: NP137 (anti-Netrin-1 monoclonal antibody)

6.2 Biomarker implementation: hepatocellular carcinoma (HCC) observational cohort

6.3 Human genetic/disease associations (curated)

7) Statistics and data highlights from recent studies

8) Expert opinions / authoritative synthesis (2024 review perspective)

9) Summary for functional annotation (NTN1 / Netrin-1)

Recent 2023–2024 evidence map (key studies)

Translational/clinical landscape (trials + curated genetic links)

Citations

📄 View Raw YAML