NTN3 encodes netrin-3, a secreted laminin-related axon-guidance ligand containing an N-terminal laminin domain, laminin EGF-like repeats and a C-terminal NTR domain. Mouse netrin-3, the established ortholog of human NTN3/NTN2L, binds DCC, neogenin and UNC5 receptors, with lower affinity for DCC than the other tested receptors, and can promote commissural axon outgrowth. Mouse developmental expression and assays suggest a prominent role in peripheral nerve development; the original human gene study detected transcript in spinal cord without establishing exclusive expression there.
| 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. 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/NTN3/NTN3-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. 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/NTN3/NTN3-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. 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/NTN3/NTN3-uniprot.txt Netrins control guidance of CNS commissural axons |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: A broad cytoplasmic assignment can include the intracellular secretory pathway. Reason: Cytoplasm includes the endomembrane system, so this term is compatible with secretory trafficking; it does not require soluble mature netrin-3 in the cytosol. Primary extracellular function does not disprove an intracellular pool, although the present rule-derived assignment is not its core functional location. Supporting Evidence: file:human/NTN3/NTN3-uniprot.txt Secreted, extracellular space, extracellular |
| GO:0007409 axonogenesis | IEA GO_REF:0000117 | ACCEPT | Summary: This annotation is appropriate but could be more specific. NTN3 is a netrin family member that functions in axon guidance, which is a subprocess of axonogenesis. The ARBA annotation captures a relevant biological process for this protein. Reason: Netrins are well-established axon guidance cues that regulate axonogenesis by guiding the growth and direction of axons during neural development. While GO:0007411 (axon guidance) is more specific, axonogenesis is an appropriate broader term. The annotation aligns with established netrin family function. Supporting Evidence: UniProt:O00634 -!- FUNCTION: Netrins control guidance of CNS commissural axons and peripheral motor axons. PMID:9143507 The netrins define a family of chemotropic factors that have been shown to play a central role in axon guidance. PMID:10366627 murine netrin-3 protein binds to netrin receptors |
| GO:0005515 protein binding | IPI PMID:26190107 A Floor-Plate Extracellular Protein-Protein Interaction Scre... | REMOVE | Summary: The DRAXIN interaction is informative evidence but generic protein binding is not a specific function. Reason: Keep the observed interaction as context; remove the uninformative protein-binding term under project policy. DRAXIN binding should not be relabeled as binding a canonical netrin receptor. Supporting Evidence: PMID:26190107 The assembled floor-plate network contains 47 interactions including the hitherto-not-reported interaction between Netrin-1 and Draxin. UniProt:O00634 O00634; Q8NBI3: DRAXIN; NbExp=2; IntAct=EBI-10831998, EBI-10827752 |
| GO:0005102 signaling receptor binding | IEA GO_REF:0000107 | MODIFY | Summary: Specific netrin-receptor binding is supported by direct mouse ortholog assays. Reason: PMID:10366627 directly tests mouse netrin-3 binding to DCC, neogenin and UNC5H1/H2/H3 and establishes orthology to human NTN2L/NTN3. Refine the existing receptor-binding term instead of adding a redundant descendant annotation. Proposed replacements: netrin receptor binding Supporting Evidence: PMID:10366627 murine netrin-3 protein binds to netrin receptors |
| GO:0005576 extracellular region | IEA GO_REF:0000107 | ACCEPT | Summary: This annotation is correct and represents a core localization for NTN3. The protein contains a signal peptide and is secreted to the extracellular space where it functions as an axon guidance cue. Reason: NTN3 is a secreted protein (signal peptide residues 1-27) that localizes to the extracellular region, specifically the extracellular matrix. This is the primary functional localization for netrin family proteins where they establish chemotropic gradients for axon guidance. Supporting Evidence: UniProt:O00634 -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular matrix |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This annotation is acceptable as NTN3 is a secreted protein that transits through the Golgi apparatus during biosynthesis. The annotation likely reflects Golgi localization during the secretory pathway. Reason: As a secreted protein, NTN3 passes through the Golgi apparatus during biosynthesis and maturation. While this is not the final functional localization, it is a valid component of the secretory pathway that NTN3 uses. The annotation is not incorrect but represents transient localization rather than core function. Supporting Evidence: UniProt:O00634 -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular matrix |
| GO:0007411 axon guidance | NAS PMID:9143507 The NTN2L gene encoding a novel human netrin maps to the aut... | ACCEPT | Summary: This is a core annotation for NTN3 supported by the primary characterization paper. PMID:9143507 describes NTN3 (then called NTN2L) as a member of the netrin family of chemotropic factors that play a central role in axon guidance. The annotation appropriately captures the primary biological function of this protein. Reason: Axon guidance is the core biological function of netrin family proteins including NTN3. The cited paper (PMID:9143507) explicitly states that netrins play a central role in axon guidance. This is well-supported by the literature on netrin family function. Supporting Evidence: PMID:9143507 The netrins define a family of chemotropic factors that have been shown to play a central role in axon guidance. UniProt:O00634 -!- FUNCTION: Netrins control guidance of CNS commissural axons and peripheral motor axons. PMID:10366627 murine netrin-3 protein binds to netrin receptors |
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Download this section (compressed HTML)Q: Has NTN3-specific receptor binding been characterized, or is receptor binding inferred from netrin-1 studies? Most functional studies focus on NTN1 (Netrin-1). Direct evidence for NTN3-receptor interactions would strengthen annotations.
Q: What is the functional relationship between NTN3 and DRAXIN in axon guidance? PMID:26190107 shows netrin-DRAXIN interaction. Understanding if this applies specifically to NTN3 would inform annotation.
Experiment: Receptor binding assays to confirm NTN3 binds DCC and UNC5 receptors directly. This would provide direct evidence for GO:1990890 annotation specific to NTN3.
Experiment: Axon guidance assays in NTN3 knockout or knockdown models to confirm NTN3 specifically functions in axon guidance rather than relying on family membership inference.
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