{"gene":"CNTN6","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2004,"finding":"NB-3 (CNTN6) acts as a functional ligand of Notch1 and triggers nuclear translocation of the Notch intracellular domain (NICD), promoting oligodendrogliogenesis from progenitor cells and differentiation of oligodendrocyte precursor cells via Deltex1. NB-3 also increases myelin-associated glycoprotein transcripts in primary oligodendrocytes.","method":"Cell-based signaling assays, nuclear translocation of NICD measured in primary cells, transcript analysis in primary oligodendrocytes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based assays with defined pathway placement (Notch/Deltex1), single lab, multiple readouts","pmids":["15082708"],"is_preprint":false},{"year":2007,"finding":"NB-3 (CNTN6) directly associates with CHL1 (Close Homolog of L1), enhancing CHL1's cell surface expression. Both CHL1 and NB-3 interact with protein tyrosine phosphatase alpha (PTPα) and regulate its activity. This signaling complex mediates proper apical dendrite orientation of deep layer pyramidal neurons in the developing visual cortex.","method":"Co-immunoprecipitation, NB-3-deficient mouse analysis showing misoriented apical dendrites, PTPα activity assays, genetic epistasis with PTPα knockout mice","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP for protein-protein interactions, multiple knockout mouse models showing convergent phenotypes, PTPα activity assay, replicated across CHL1/NB-3/PTPα triple analysis","pmids":["18046458"],"is_preprint":false},{"year":2003,"finding":"NB-3 (CNTN6) is required for normal motor coordination in mice. NB-3-deficient mice show impaired motor learning on rotarod, and dysfunction in equilibrium and vestibular function, despite normal brain architecture, establishing an in vivo functional role in cerebellar-dependent motor function.","method":"NB-3 knockout mouse generation (LacZ knockin), behavioral tests (rotarod, wire hang, horizontal rod-walking), brain histology","journal":"Journal of neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined behavioral phenotype and histological controls, multiple behavioral paradigms in single rigorous study","pmids":["12884264"],"is_preprint":false},{"year":2009,"finding":"NB-3 (CNTN6) is localized presynaptically at glutamatergic synapses between parallel fibers and Purkinje cells (co-localizing with VGLUT1, apposed to mGluR1α). NB-3 deficiency reduces the density of parallel fiber synaptic terminals and increases caspase-dependent cell death in the developing cerebellum, establishing a role in synapse formation.","method":"Immunohistochemistry with synaptic markers (VGLUT1, mGluR1α), NB-3 knockout mouse analysis, quantification of synapse density and caspase-dependent death at postnatal time points","journal":"Developmental neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — presynaptic localization established by co-localization with established markers, NB-3 KO with quantitative synaptic phenotype, multiple time points","pmids":["19672956"],"is_preprint":false},{"year":2010,"finding":"NB-3 (CNTN6) is localized to presynaptic glutamatergic (but not GABAergic) terminals in the hippocampal formation. NB-3 deficiency selectively reduces the density of VGLUT1- and VGLUT2-positive puncta by ~20–30% in regions of high NB-3 expression, without affecting VGAT-positive inhibitory synapses, establishing a selective role in excitatory synapse formation.","method":"Immunohistochemistry with vesicular transporter markers (VGLUT1, VGLUT2, VGAT), NB-3 knockout mouse quantification of synaptic puncta density","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — NB-3 KO with quantitative synaptic phenotype using multiple markers, single lab","pmids":["20176085"],"is_preprint":false},{"year":2011,"finding":"PTPα (receptor-like protein-tyrosine phosphatase alpha) regulates cell surface expression of NB-3 (CNTN6) by facilitating Golgi exit and stabilizing NB-3 at the plasma membrane. This effect requires the extracellular domain of PTPα but not its catalytic activity. PTPα knockout cortical neurons show reduced NB-3 at the cell surface.","method":"Co-expression in COS1 cells, PTPα knockout neuron analysis, subcellular fractionation, domain deletion mutants of PTPα","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis plus KO neurons plus heterologous expression, single lab, multiple orthogonal methods","pmids":["21622556"],"is_preprint":false},{"year":2012,"finding":"NB-3 (CNTN6) is expressed in corticospinal tract (CST) axons and its loss delays both the normal projection of CST axons (from embryonic to postnatal stages) and their terminal branching into spinal gray matter, without ultimately preventing final trajectory completion by P21 (projection) or P45 (innervation area).","method":"Axon tracing in NB-3 knockout mice at multiple developmental time points, immunohistochemistry for NB-3 in CST trajectory, quantification of innervation area in spinal gray matter","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with axon tracing at multiple developmental time points, single lab","pmids":["21935948"],"is_preprint":false},{"year":2011,"finding":"NB-3 (CNTN6) as a substrate promotes neuronal survival and neurite outgrowth in vitro, partly through homophilic mechanisms. NB-3 deficiency renders neurons more susceptible to oxygen-glucose deprivation and leads to increased infarct volume after MCAO in vivo.","method":"In vitro neuronal culture on NB-3 substrate, NB-3 knockout neuron survival and neurite outgrowth assays, oxygen-glucose deprivation, in vivo MCAO in NB-3 knockout mice with TTC staining","journal":"Stroke","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro substrate assay plus in vivo KO model with quantitative phenotype, single lab","pmids":["21817151"],"is_preprint":false},{"year":2014,"finding":"Adropin interacts with NB-3 (CNTN6) at the plasma membrane, identified by yeast two-hybrid screening and validated in vivo. This interaction promotes NB-3-induced Notch signaling activation and expression of Notch target genes. Adropin knockout mice phenocopy NB-3 knockout mice with decreased locomotor activity, impaired motor coordination, and defective synapse formation.","method":"Yeast two-hybrid screening, adropin knockout mouse generation and behavioral/synaptic phenotyping, Notch target gene expression assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus KO mouse phenocopy convergence, single lab, Notch pathway readout","pmids":["25074942"],"is_preprint":false},{"year":2018,"finding":"NB-3 (CNTN6) is induced in both serotonergic raphespinal tract (sRST) axons and scar-forming cells after spinal cord injury. Blocking NB-3 expression in either sRST axons or scar-forming cells promotes axonal regrowth past the glial scar, synapse reformation between sRST axons and motor neurons, and enhanced motor function, demonstrating that NB-3 induction in both cell types mediates inhibition of sRST axon regeneration.","method":"In vivo spinal cord transection model, NB-3 knockdown/deficiency in sRST axons and scar cells, synapse reformation analysis, electrophysiological assessment of motor activity","journal":"Journal of neurotrauma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific loss-of-function in vivo with synaptic and functional readouts, single lab","pmids":["30156464"],"is_preprint":false},{"year":2022,"finding":"NB-3 (CNTN6) is expressed in brain microvascular endothelial cells (BMECs) and responds to hypoxia. Endothelial-specific conditional knockout of NB-3 increases blood-brain barrier (BBB) leakage and downregulates tight junction proteins in vivo. NB-3 regulates Notch signaling in endothelial cells; blocking Notch increases VEGF/VEGFR2 pathway activation under LPS/hypoxia. Overexpression or supplementation with NB-3 alleviates endothelial barrier injury.","method":"Conditional endothelial NB-3 knockout mice, BBB permeability assays, tight junction protein immunoblotting, transcriptome sequencing, Notch pathway inhibition experiments in vitro","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with BBB phenotype, transcriptomic pathway analysis, gain-of-function rescue, single lab","pmids":["35584741"],"is_preprint":false},{"year":2000,"finding":"The mouse NB-3 (CNTN6) gene consists of 23 exons spanning >130 kb, with a 1.2 kb upstream fragment sufficient for basal promoter activity. An alternative splice isoform lacking residues 62–78 (part of the first Ig-like domain) was identified. NB-3 mRNA expression is developmentally regulated: increasing postnatally in cerebellum to adulthood, while declining in cerebrum after P7.","method":"Reporter gene analysis (promoter activity), RT-PCR and Northern blot for splice isoform identification, in situ hybridization, gene structure determination","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay for promoter, structural gene analysis, in situ hybridization, single lab with multiple methods","pmids":["10717476"],"is_preprint":false},{"year":2025,"finding":"The CNTN6 locus is involved in lumenization and radial glial cell fate determination during early human cortical development. CNTN6 variants alter radial glial cell proliferation and identity, and affect nuclear-cytoplasmic translocation of PAX6, a key forebrain transcription factor. CNTN6 partially functions through the Notch signaling pathway in early human brain development.","method":"Human cerebral organoids, iPSC reprogramming, CRISPR/Cas9 genome editing, immunofluorescence for radial glial markers and PAX6 localization, Notch pathway analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — human cerebral organoid/CRISPR system with multiple readouts but preprint (not peer-reviewed), single lab","pmids":["bio_10.1101_2025.10.09.681391"],"is_preprint":true}],"current_model":"CNTN6 (NB-3) is a GPI-anchored, brain-expressed cell adhesion molecule of the contactin/immunoglobulin superfamily that functions as a non-canonical Notch1 ligand (triggering NICD nuclear translocation via Deltex1 to promote oligodendrocyte differentiation), forms a signaling complex with CHL1 and PTPα to regulate apical dendrite orientation, localizes presynaptically at glutamatergic synapses to promote excitatory synapse formation in cerebellum and hippocampus, guides corticospinal tract axon projection and branching, supports neuronal survival and neurite outgrowth partly through homophilic mechanisms, maintains blood-brain barrier integrity in endothelial cells via Notch signaling, and interacts with adropin at the plasma membrane to modulate Notch-dependent cerebellar development and motor coordination."},"narrative":{"mechanistic_narrative":"CNTN6 (NB-3) is a brain-expressed cell adhesion molecule of the contactin/immunoglobulin superfamily that functions as a developmental regulator of neuronal differentiation, synapse formation, and axon guidance, acting in large part as a non-canonical activator of Notch signaling [PMID:15082708, PMID:19672956]. As a functional Notch1 ligand, NB-3 triggers nuclear translocation of the Notch intracellular domain via Deltex1, driving oligodendrocyte precursor differentiation and oligodendrogliogenesis [PMID:15082708]; this Notch-activating activity is potentiated by its plasma-membrane partner adropin, whose loss phenocopies NB-3 deficiency in motor coordination and synapse formation [PMID:25074942]. NB-3 directly associates with the adhesion molecule CHL1 and the receptor phosphatase PTPα to form a signaling complex that governs apical dendrite orientation of cortical pyramidal neurons, while PTPα reciprocally promotes NB-3 Golgi exit and cell-surface stabilization independent of its catalytic activity [PMID:18046458, PMID:21622556]. At glutamatergic synapses, NB-3 localizes presynaptically and selectively promotes excitatory synapse formation in cerebellum and hippocampus, with its loss reducing VGLUT-positive terminal density and increasing caspase-dependent neuronal death [PMID:19672956, PMID:20176085]. In vivo, NB-3 is required for cerebellar-dependent motor coordination [PMID:12884264], guides corticospinal tract axon projection and terminal branching [PMID:21935948], supports neuronal survival and neurite outgrowth partly through homophilic mechanisms [PMID:21817151], and maintains blood-brain barrier integrity in endothelial cells through Notch-dependent regulation of tight junctions [PMID:35584741].","teleology":[{"year":2000,"claim":"Establishing the gene structure, promoter, and developmentally regulated expression of NB-3 provided the molecular foundation for studying its tissue-specific neural roles.","evidence":"Reporter assays, RT-PCR/Northern blot, and in situ hybridization of the mouse gene","pmids":["10717476"],"confidence":"Medium","gaps":["Functional role of the splice isoform lacking Ig-domain residues 62–78 unresolved","No protein-level functional assignment from this study"]},{"year":2003,"claim":"A clean knockout demonstrated that NB-3 is required in vivo for cerebellar-dependent motor coordination, moving it from an expressed molecule to a functional necessity.","evidence":"LacZ-knockin NB-3 knockout mice with rotarod, equilibrium, and histological controls","pmids":["12884264"],"confidence":"High","gaps":["Cellular/molecular basis of the motor phenotype not defined at this stage","Normal gross brain architecture left the mechanism unexplained"]},{"year":2004,"claim":"Identifying NB-3 as a functional Notch1 ligand that drives NICD nuclear translocation via Deltex1 placed it within a defined signaling pathway controlling oligodendrocyte differentiation.","evidence":"Cell-based signaling assays, NICD translocation, and transcript analysis in primary oligodendrocytes","pmids":["15082708"],"confidence":"Medium","gaps":["Direct receptor-ligand binding not structurally resolved","In vivo requirement for NB-3 in oligodendrogliogenesis not tested here"]},{"year":2007,"claim":"Defining a CHL1–NB-3–PTPα complex explained how NB-3 transduces adhesion signals to control apical dendrite orientation in the cortex.","evidence":"Reciprocal co-IP, PTPα activity assays, and convergent knockout mouse phenotypes","pmids":["18046458"],"confidence":"High","gaps":["Downstream effectors linking PTPα activity to dendrite orientation not fully mapped","Whether Notch signaling intersects this complex unaddressed"]},{"year":2009,"claim":"Localizing NB-3 to presynaptic glutamatergic terminals and showing reduced synapse density plus increased cell death on its loss established a role in cerebellar excitatory synapse formation.","evidence":"Immunohistochemistry with synaptic markers and quantitative synapse/apoptosis analysis in NB-3 KO cerebellum","pmids":["19672956"],"confidence":"High","gaps":["Molecular partner mediating presynaptic function unknown","Causal link between synapse loss and cell death not dissected"]},{"year":2010,"claim":"Extending presynaptic localization to hippocampus and showing selective loss of VGLUT but not VGAT puncta established NB-3 as a specific regulator of excitatory, not inhibitory, synapses.","evidence":"Immunohistochemistry with VGLUT1/2 and VGAT markers and puncta quantification in NB-3 KO","pmids":["20176085"],"confidence":"Medium","gaps":["Mechanism of excitatory selectivity unexplained","Functional/electrophysiological consequences not measured"]},{"year":2011,"claim":"Showing PTPα promotes NB-3 Golgi exit and surface stabilization via its extracellular domain clarified how the complex regulates NB-3 trafficking independently of phosphatase activity.","evidence":"Heterologous co-expression, PTPα KO neurons, subcellular fractionation, and domain-deletion mutants","pmids":["21622556"],"confidence":"Medium","gaps":["Structural basis of the PTPα ectodomain–NB-3 interaction unknown","Whether trafficking control is required for the dendrite phenotype untested"]},{"year":2011,"claim":"Demonstrating that NB-3 promotes neuronal survival/neurite outgrowth and protects against ischemic injury extended its role to neuroprotection.","evidence":"In vitro NB-3 substrate assays, oxygen-glucose deprivation, and in vivo MCAO in NB-3 KO mice","pmids":["21817151"],"confidence":"Medium","gaps":["Receptor mediating homophilic survival signaling not identified","Pathway linking NB-3 to ischemic protection undefined"]},{"year":2012,"claim":"Axon tracing in knockouts showed NB-3 accelerates corticospinal tract projection and terminal branching, assigning it a timing role in motor axon development.","evidence":"Axon tracing and innervation quantification in NB-3 KO mice across developmental stages","pmids":["21935948"],"confidence":"Medium","gaps":["Molecular guidance partners in CST axons unknown","Final trajectory is rescued by P21/P45, leaving the long-term consequence unclear"]},{"year":2014,"claim":"Identifying adropin as a plasma-membrane partner that potentiates NB-3-induced Notch signaling, with adropin KO phenocopying NB-3 KO, established a ligand cooperating with NB-3 in cerebellar development.","evidence":"Yeast two-hybrid screen, adropin KO behavioral/synaptic phenotyping, and Notch target gene assays","pmids":["25074942"],"confidence":"Medium","gaps":["Structural basis of the adropin–NB-3 interaction unresolved","How adropin enhances Notch activation mechanistically unknown"]},{"year":2018,"claim":"Showing NB-3 induction in both raphespinal axons and scar cells inhibits regeneration revealed a context-dependent, growth-inhibitory role after CNS injury.","evidence":"Spinal cord transection with cell-type-specific NB-3 loss-of-function, synapse reformation, and electrophysiology","pmids":["30156464"],"confidence":"Medium","gaps":["Receptor mediating the inhibitory signal not identified","Relationship to NB-3's developmental pro-growth roles unreconciled"]},{"year":2022,"claim":"Endothelial conditional knockout established a non-neuronal role: NB-3 maintains blood-brain barrier integrity through Notch-dependent control of tight junctions.","evidence":"Endothelial-specific NB-3 cKO, BBB permeability assays, tight-junction immunoblotting, transcriptomics, and Notch inhibition in vitro","pmids":["35584741"],"confidence":"Medium","gaps":["Direct Notch ligand-receptor engagement in endothelium not demonstrated","Link between NB-3 Notch signaling and VEGF/VEGFR2 suppression mechanistically incomplete"]},{"year":2025,"claim":"Human cerebral organoid work implicated CNTN6 in radial glial fate, PAX6 nuclear-cytoplasmic localization, and lumenization, extending its Notch-linked role to early human cortical development.","evidence":"iPSC-derived cerebral organoids with CRISPR editing, radial glial marker and PAX6 immunofluorescence, and Notch pathway analysis (preprint)","pmids":["bio_10.1101_2025.10.09.681391"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Mechanism connecting CNTN6 to PAX6 translocation undefined","Human relevance not validated in vivo"]},{"year":null,"claim":"The identity of the direct receptor(s) mediating NB-3 homophilic and heterophilic signaling across its diverse roles, and the structural basis of its Notch1 and adropin interactions, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of NB-3 in complex with Notch1, adropin, CHL1, or PTPα","How a single GPI-anchored adhesion molecule switches between pro-growth and growth-inhibitory outputs is unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,7]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[],"complexes":["CHL1–NB-3–PTPα signaling complex"],"partners":["CHL1","PTPRA","NOTCH1","DTX1","ENHO"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UQ52","full_name":"Contactin-6","aliases":["Neural recognition molecule NB-3","hNB-3"],"length_aa":1028,"mass_kda":114.0,"function":"Contactins mediate cell surface interactions during nervous system development. Participates in oligodendrocytes generation by acting as a ligand of NOTCH1. Its association with NOTCH1 promotes NOTCH1 activation through the released notch intracellular domain (NICD) and subsequent translocation to the nucleus. Involved in motor coordination (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UQ52/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CNTN6","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CNTN6","total_profiled":1310},"omim":[{"mim_id":"607220","title":"CONTACTIN 6; CNTN6","url":"https://www.omim.org/entry/607220"},{"mim_id":"607219","title":"CONTACTIN 5; CNTN5","url":"https://www.omim.org/entry/607219"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"adrenal gland","ntpm":3.2},{"tissue":"brain","ntpm":8.8},{"tissue":"thyroid gland","ntpm":9.0}],"url":"https://www.proteinatlas.org/search/CNTN6"},"hgnc":{"alias_symbol":["NB-3"],"prev_symbol":[]},"alphafold":{"accession":"Q9UQ52","domains":[{"cath_id":"2.60.40.10","chopping":"23-118","consensus_level":"high","plddt":88.0,"start":23,"end":118},{"cath_id":"2.60.40.10","chopping":"139-223","consensus_level":"medium","plddt":89.2573,"start":139,"end":223},{"cath_id":"2.60.40.10","chopping":"225-317","consensus_level":"medium","plddt":94.0855,"start":225,"end":317},{"cath_id":"2.60.40.10","chopping":"323-403","consensus_level":"high","plddt":92.6975,"start":323,"end":403},{"cath_id":"2.60.40.10","chopping":"406-496","consensus_level":"high","plddt":88.6412,"start":406,"end":496},{"cath_id":"2.60.40.10","chopping":"503-594","consensus_level":"high","plddt":86.9845,"start":503,"end":594},{"cath_id":"2.60.40.10","chopping":"601-694","consensus_level":"high","plddt":92.8891,"start":601,"end":694},{"cath_id":"2.60.40.10","chopping":"704-796","consensus_level":"high","plddt":89.8167,"start":704,"end":796},{"cath_id":"2.60.40.10","chopping":"806-896","consensus_level":"medium","plddt":85.9841,"start":806,"end":896}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQ52","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQ52-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQ52-F1-predicted_aligned_error_v6.png","plddt_mean":86.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CNTN6","jax_strain_url":"https://www.jax.org/strain/search?query=CNTN6"},"sequence":{"accession":"Q9UQ52","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UQ52.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UQ52/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQ52"}},"corpus_meta":[{"pmid":"15082708","id":"PMC_15082708","title":"NB-3/Notch1 pathway via Deltex1 promotes neural progenitor cell differentiation into oligodendrocytes.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15082708","citation_count":122,"is_preprint":false},{"pmid":"25074942","id":"PMC_25074942","title":"Adropin is a brain membrane-bound protein regulating physical activity via the NB-3/Notch signaling pathway in mice.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25074942","citation_count":108,"is_preprint":false},{"pmid":"18046458","id":"PMC_18046458","title":"Neural recognition molecules CHL1 and NB-3 regulate apical dendrite orientation in the neocortex via PTP alpha.","date":"2007","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/18046458","citation_count":74,"is_preprint":false},{"pmid":"12884264","id":"PMC_12884264","title":"Impaired motor coordination in mice lacking neural recognition molecule NB-3 of the contactin/F3 subgroup.","date":"2003","source":"Journal of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/12884264","citation_count":62,"is_preprint":false},{"pmid":"26257835","id":"PMC_26257835","title":"CNTN6 copy number variations in 14 patients: a possible candidate gene for neurodevelopmental and neuropsychiatric disorders.","date":"2015","source":"Journal of neurodevelopmental disorders","url":"https://pubmed.ncbi.nlm.nih.gov/26257835","citation_count":61,"is_preprint":false},{"pmid":"27166760","id":"PMC_27166760","title":"CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders.","date":"2016","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/27166760","citation_count":58,"is_preprint":false},{"pmid":"19672956","id":"PMC_19672956","title":"Contribution of the neural cell recognition molecule NB-3 to synapse formation between parallel fibers and Purkinje cells in mouse.","date":"2009","source":"Developmental neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/19672956","citation_count":57,"is_preprint":false},{"pmid":"10717476","id":"PMC_10717476","title":"Expression and regulation of a gene encoding neural recognition molecule NB-3 of the contactin/F3 subgroup in mouse brain.","date":"2000","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/10717476","citation_count":50,"is_preprint":false},{"pmid":"25606055","id":"PMC_25606055","title":"Single gene microdeletions and microduplication of 3p26.3 in three unrelated families: CNTN6 as a new candidate gene for intellectual disability.","date":"2014","source":"Molecular cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/25606055","citation_count":46,"is_preprint":false},{"pmid":"20176085","id":"PMC_20176085","title":"Synaptic formation in subsets of glutamatergic terminals in the mouse hippocampal formation is affected by a deficiency in the neural cell recognition molecule NB-3.","date":"2010","source":"Neuroscience 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33897758","citation_count":8,"is_preprint":false},{"pmid":"29983269","id":"PMC_29983269","title":"Schizophrenia and epilepsy as a result of maternally inherited CNTN6 copy number variant.","date":"2018","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/29983269","citation_count":8,"is_preprint":false},{"pmid":"31578377","id":"PMC_31578377","title":"Time origin and structural analysis of the induced CRISPR/cas9 megabase-sized deletions and duplications involving the Cntn6 gene in mice.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31578377","citation_count":7,"is_preprint":false},{"pmid":"35584741","id":"PMC_35584741","title":"NB-3 expression in endothelial cells contributes to the maintenance of blood brain barrier integrity in a mouse high-altitude cerebral edema model.","date":"2022","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35584741","citation_count":6,"is_preprint":false},{"pmid":"31098770","id":"PMC_31098770","title":"Decreased Expression of Synaptophysin 1 (SYP1 Major Synaptic Vesicle Protein p38) and Contactin 6 (CNTN6/NB3) in the Cerebellar Vermis of reln Haplodeficient Mice.","date":"2019","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/31098770","citation_count":4,"is_preprint":false},{"pmid":"30156464","id":"PMC_30156464","title":"Induced NB-3 Limits Regenerative Potential of Serotonergic Axons after Complete Spinal Transection.","date":"2018","source":"Journal of neurotrauma","url":"https://pubmed.ncbi.nlm.nih.gov/30156464","citation_count":4,"is_preprint":false},{"pmid":"31518906","id":"PMC_31518906","title":"Generation of the induced pluripotent stem cell line, ICAGi002-A, from unaffected carrier megabase scaled duplication involving the CNTN6 gene.","date":"2019","source":"Stem cell 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and Magnetism of U2+Ni21-B6 and Nb3-Ni20+B6 and the Role of Uranium in the Formation of the Quaternary U2-NbNi21B6 and UδNb3-δNi20B6 Systems.","date":"2019","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31675217","citation_count":1,"is_preprint":false},{"pmid":"42100732","id":"PMC_42100732","title":"Role of CNTN6 in neurodevelopment and neuropathology.","date":"2026","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/42100732","citation_count":0,"is_preprint":false},{"pmid":"38487518","id":"PMC_38487518","title":"The effects of Sr-substitution in Ba2SmTi2Nb3O15 ceramics: structural study, optical properties, and complex impedance spectroscopy.","date":"2024","source":"RSC advances","url":"https://pubmed.ncbi.nlm.nih.gov/38487518","citation_count":0,"is_preprint":false},{"pmid":"33647891","id":"PMC_33647891","title":"A15 Nb3Si: a 'high'Tcsuperconductor synthesized at a pressure of one megabar and metastable at ambient 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NB-3 also increases myelin-associated glycoprotein transcripts in primary oligodendrocytes.\",\n      \"method\": \"Cell-based signaling assays, nuclear translocation of NICD measured in primary cells, transcript analysis in primary oligodendrocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based assays with defined pathway placement (Notch/Deltex1), single lab, multiple readouts\",\n      \"pmids\": [\"15082708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NB-3 (CNTN6) directly associates with CHL1 (Close Homolog of L1), enhancing CHL1's cell surface expression. Both CHL1 and NB-3 interact with protein tyrosine phosphatase alpha (PTPα) and regulate its activity. This signaling complex mediates proper apical dendrite orientation of deep layer pyramidal neurons in the developing visual cortex.\",\n      \"method\": \"Co-immunoprecipitation, NB-3-deficient mouse analysis showing misoriented apical dendrites, PTPα activity assays, genetic epistasis with PTPα knockout mice\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP for protein-protein interactions, multiple knockout mouse models showing convergent phenotypes, PTPα activity assay, replicated across CHL1/NB-3/PTPα triple analysis\",\n      \"pmids\": [\"18046458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NB-3 (CNTN6) is required for normal motor coordination in mice. NB-3-deficient mice show impaired motor learning on rotarod, and dysfunction in equilibrium and vestibular function, despite normal brain architecture, establishing an in vivo functional role in cerebellar-dependent motor function.\",\n      \"method\": \"NB-3 knockout mouse generation (LacZ knockin), behavioral tests (rotarod, wire hang, horizontal rod-walking), brain histology\",\n      \"journal\": \"Journal of neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined behavioral phenotype and histological controls, multiple behavioral paradigms in single rigorous study\",\n      \"pmids\": [\"12884264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NB-3 (CNTN6) is localized presynaptically at glutamatergic synapses between parallel fibers and Purkinje cells (co-localizing with VGLUT1, apposed to mGluR1α). NB-3 deficiency reduces the density of parallel fiber synaptic terminals and increases caspase-dependent cell death in the developing cerebellum, establishing a role in synapse formation.\",\n      \"method\": \"Immunohistochemistry with synaptic markers (VGLUT1, mGluR1α), NB-3 knockout mouse analysis, quantification of synapse density and caspase-dependent death at postnatal time points\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — presynaptic localization established by co-localization with established markers, NB-3 KO with quantitative synaptic phenotype, multiple time points\",\n      \"pmids\": [\"19672956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NB-3 (CNTN6) is localized to presynaptic glutamatergic (but not GABAergic) terminals in the hippocampal formation. NB-3 deficiency selectively reduces the density of VGLUT1- and VGLUT2-positive puncta by ~20–30% in regions of high NB-3 expression, without affecting VGAT-positive inhibitory synapses, establishing a selective role in excitatory synapse formation.\",\n      \"method\": \"Immunohistochemistry with vesicular transporter markers (VGLUT1, VGLUT2, VGAT), NB-3 knockout mouse quantification of synaptic puncta density\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — NB-3 KO with quantitative synaptic phenotype using multiple markers, single lab\",\n      \"pmids\": [\"20176085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PTPα (receptor-like protein-tyrosine phosphatase alpha) regulates cell surface expression of NB-3 (CNTN6) by facilitating Golgi exit and stabilizing NB-3 at the plasma membrane. This effect requires the extracellular domain of PTPα but not its catalytic activity. PTPα knockout cortical neurons show reduced NB-3 at the cell surface.\",\n      \"method\": \"Co-expression in COS1 cells, PTPα knockout neuron analysis, subcellular fractionation, domain deletion mutants of PTPα\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis plus KO neurons plus heterologous expression, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21622556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NB-3 (CNTN6) is expressed in corticospinal tract (CST) axons and its loss delays both the normal projection of CST axons (from embryonic to postnatal stages) and their terminal branching into spinal gray matter, without ultimately preventing final trajectory completion by P21 (projection) or P45 (innervation area).\",\n      \"method\": \"Axon tracing in NB-3 knockout mice at multiple developmental time points, immunohistochemistry for NB-3 in CST trajectory, quantification of innervation area in spinal gray matter\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with axon tracing at multiple developmental time points, single lab\",\n      \"pmids\": [\"21935948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NB-3 (CNTN6) as a substrate promotes neuronal survival and neurite outgrowth in vitro, partly through homophilic mechanisms. NB-3 deficiency renders neurons more susceptible to oxygen-glucose deprivation and leads to increased infarct volume after MCAO in vivo.\",\n      \"method\": \"In vitro neuronal culture on NB-3 substrate, NB-3 knockout neuron survival and neurite outgrowth assays, oxygen-glucose deprivation, in vivo MCAO in NB-3 knockout mice with TTC staining\",\n      \"journal\": \"Stroke\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro substrate assay plus in vivo KO model with quantitative phenotype, single lab\",\n      \"pmids\": [\"21817151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Adropin interacts with NB-3 (CNTN6) at the plasma membrane, identified by yeast two-hybrid screening and validated in vivo. This interaction promotes NB-3-induced Notch signaling activation and expression of Notch target genes. Adropin knockout mice phenocopy NB-3 knockout mice with decreased locomotor activity, impaired motor coordination, and defective synapse formation.\",\n      \"method\": \"Yeast two-hybrid screening, adropin knockout mouse generation and behavioral/synaptic phenotyping, Notch target gene expression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus KO mouse phenocopy convergence, single lab, Notch pathway readout\",\n      \"pmids\": [\"25074942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NB-3 (CNTN6) is induced in both serotonergic raphespinal tract (sRST) axons and scar-forming cells after spinal cord injury. Blocking NB-3 expression in either sRST axons or scar-forming cells promotes axonal regrowth past the glial scar, synapse reformation between sRST axons and motor neurons, and enhanced motor function, demonstrating that NB-3 induction in both cell types mediates inhibition of sRST axon regeneration.\",\n      \"method\": \"In vivo spinal cord transection model, NB-3 knockdown/deficiency in sRST axons and scar cells, synapse reformation analysis, electrophysiological assessment of motor activity\",\n      \"journal\": \"Journal of neurotrauma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific loss-of-function in vivo with synaptic and functional readouts, single lab\",\n      \"pmids\": [\"30156464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NB-3 (CNTN6) is expressed in brain microvascular endothelial cells (BMECs) and responds to hypoxia. Endothelial-specific conditional knockout of NB-3 increases blood-brain barrier (BBB) leakage and downregulates tight junction proteins in vivo. NB-3 regulates Notch signaling in endothelial cells; blocking Notch increases VEGF/VEGFR2 pathway activation under LPS/hypoxia. Overexpression or supplementation with NB-3 alleviates endothelial barrier injury.\",\n      \"method\": \"Conditional endothelial NB-3 knockout mice, BBB permeability assays, tight junction protein immunoblotting, transcriptome sequencing, Notch pathway inhibition experiments in vitro\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with BBB phenotype, transcriptomic pathway analysis, gain-of-function rescue, single lab\",\n      \"pmids\": [\"35584741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The mouse NB-3 (CNTN6) gene consists of 23 exons spanning >130 kb, with a 1.2 kb upstream fragment sufficient for basal promoter activity. An alternative splice isoform lacking residues 62–78 (part of the first Ig-like domain) was identified. NB-3 mRNA expression is developmentally regulated: increasing postnatally in cerebellum to adulthood, while declining in cerebrum after P7.\",\n      \"method\": \"Reporter gene analysis (promoter activity), RT-PCR and Northern blot for splice isoform identification, in situ hybridization, gene structure determination\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay for promoter, structural gene analysis, in situ hybridization, single lab with multiple methods\",\n      \"pmids\": [\"10717476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The CNTN6 locus is involved in lumenization and radial glial cell fate determination during early human cortical development. CNTN6 variants alter radial glial cell proliferation and identity, and affect nuclear-cytoplasmic translocation of PAX6, a key forebrain transcription factor. CNTN6 partially functions through the Notch signaling pathway in early human brain development.\",\n      \"method\": \"Human cerebral organoids, iPSC reprogramming, CRISPR/Cas9 genome editing, immunofluorescence for radial glial markers and PAX6 localization, Notch pathway analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — human cerebral organoid/CRISPR system with multiple readouts but preprint (not peer-reviewed), single lab\",\n      \"pmids\": [\"bio_10.1101_2025.10.09.681391\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CNTN6 (NB-3) is a GPI-anchored, brain-expressed cell adhesion molecule of the contactin/immunoglobulin superfamily that functions as a non-canonical Notch1 ligand (triggering NICD nuclear translocation via Deltex1 to promote oligodendrocyte differentiation), forms a signaling complex with CHL1 and PTPα to regulate apical dendrite orientation, localizes presynaptically at glutamatergic synapses to promote excitatory synapse formation in cerebellum and hippocampus, guides corticospinal tract axon projection and branching, supports neuronal survival and neurite outgrowth partly through homophilic mechanisms, maintains blood-brain barrier integrity in endothelial cells via Notch signaling, and interacts with adropin at the plasma membrane to modulate Notch-dependent cerebellar development and motor coordination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CNTN6 (NB-3) is a brain-expressed cell adhesion molecule of the contactin/immunoglobulin superfamily that functions as a developmental regulator of neuronal differentiation, synapse formation, and axon guidance, acting in large part as a non-canonical activator of Notch signaling [#0, #3]. As a functional Notch1 ligand, NB-3 triggers nuclear translocation of the Notch intracellular domain via Deltex1, driving oligodendrocyte precursor differentiation and oligodendrogliogenesis [#0]; this Notch-activating activity is potentiated by its plasma-membrane partner adropin, whose loss phenocopies NB-3 deficiency in motor coordination and synapse formation [#8]. NB-3 directly associates with the adhesion molecule CHL1 and the receptor phosphatase PTP\\u03b1 to form a signaling complex that governs apical dendrite orientation of cortical pyramidal neurons, while PTP\\u03b1 reciprocally promotes NB-3 Golgi exit and cell-surface stabilization independent of its catalytic activity [#1, #5]. At glutamatergic synapses, NB-3 localizes presynaptically and selectively promotes excitatory synapse formation in cerebellum and hippocampus, with its loss reducing VGLUT-positive terminal density and increasing caspase-dependent neuronal death [#3, #4]. In vivo, NB-3 is required for cerebellar-dependent motor coordination [#2], guides corticospinal tract axon projection and terminal branching [#6], supports neuronal survival and neurite outgrowth partly through homophilic mechanisms [#7], and maintains blood-brain barrier integrity in endothelial cells through Notch-dependent regulation of tight junctions [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing the gene structure, promoter, and developmentally regulated expression of NB-3 provided the molecular foundation for studying its tissue-specific neural roles.\",\n      \"evidence\": \"Reporter assays, RT-PCR/Northern blot, and in situ hybridization of the mouse gene\",\n      \"pmids\": [\"10717476\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the splice isoform lacking Ig-domain residues 62\\u201378 unresolved\", \"No protein-level functional assignment from this study\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"A clean knockout demonstrated that NB-3 is required in vivo for cerebellar-dependent motor coordination, moving it from an expressed molecule to a functional necessity.\",\n      \"evidence\": \"LacZ-knockin NB-3 knockout mice with rotarod, equilibrium, and histological controls\",\n      \"pmids\": [\"12884264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular/molecular basis of the motor phenotype not defined at this stage\", \"Normal gross brain architecture left the mechanism unexplained\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying NB-3 as a functional Notch1 ligand that drives NICD nuclear translocation via Deltex1 placed it within a defined signaling pathway controlling oligodendrocyte differentiation.\",\n      \"evidence\": \"Cell-based signaling assays, NICD translocation, and transcript analysis in primary oligodendrocytes\",\n      \"pmids\": [\"15082708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor-ligand binding not structurally resolved\", \"In vivo requirement for NB-3 in oligodendrogliogenesis not tested here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defining a CHL1\\u2013NB-3\\u2013PTP\\u03b1 complex explained how NB-3 transduces adhesion signals to control apical dendrite orientation in the cortex.\",\n      \"evidence\": \"Reciprocal co-IP, PTP\\u03b1 activity assays, and convergent knockout mouse phenotypes\",\n      \"pmids\": [\"18046458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors linking PTP\\u03b1 activity to dendrite orientation not fully mapped\", \"Whether Notch signaling intersects this complex unaddressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Localizing NB-3 to presynaptic glutamatergic terminals and showing reduced synapse density plus increased cell death on its loss established a role in cerebellar excitatory synapse formation.\",\n      \"evidence\": \"Immunohistochemistry with synaptic markers and quantitative synapse/apoptosis analysis in NB-3 KO cerebellum\",\n      \"pmids\": [\"19672956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partner mediating presynaptic function unknown\", \"Causal link between synapse loss and cell death not dissected\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extending presynaptic localization to hippocampus and showing selective loss of VGLUT but not VGAT puncta established NB-3 as a specific regulator of excitatory, not inhibitory, synapses.\",\n      \"evidence\": \"Immunohistochemistry with VGLUT1/2 and VGAT markers and puncta quantification in NB-3 KO\",\n      \"pmids\": [\"20176085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of excitatory selectivity unexplained\", \"Functional/electrophysiological consequences not measured\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showing PTP\\u03b1 promotes NB-3 Golgi exit and surface stabilization via its extracellular domain clarified how the complex regulates NB-3 trafficking independently of phosphatase activity.\",\n      \"evidence\": \"Heterologous co-expression, PTP\\u03b1 KO neurons, subcellular fractionation, and domain-deletion mutants\",\n      \"pmids\": [\"21622556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the PTP\\u03b1 ectodomain\\u2013NB-3 interaction unknown\", \"Whether trafficking control is required for the dendrite phenotype untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that NB-3 promotes neuronal survival/neurite outgrowth and protects against ischemic injury extended its role to neuroprotection.\",\n      \"evidence\": \"In vitro NB-3 substrate assays, oxygen-glucose deprivation, and in vivo MCAO in NB-3 KO mice\",\n      \"pmids\": [\"21817151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating homophilic survival signaling not identified\", \"Pathway linking NB-3 to ischemic protection undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Axon tracing in knockouts showed NB-3 accelerates corticospinal tract projection and terminal branching, assigning it a timing role in motor axon development.\",\n      \"evidence\": \"Axon tracing and innervation quantification in NB-3 KO mice across developmental stages\",\n      \"pmids\": [\"21935948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular guidance partners in CST axons unknown\", \"Final trajectory is rescued by P21/P45, leaving the long-term consequence unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying adropin as a plasma-membrane partner that potentiates NB-3-induced Notch signaling, with adropin KO phenocopying NB-3 KO, established a ligand cooperating with NB-3 in cerebellar development.\",\n      \"evidence\": \"Yeast two-hybrid screen, adropin KO behavioral/synaptic phenotyping, and Notch target gene assays\",\n      \"pmids\": [\"25074942\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the adropin\\u2013NB-3 interaction unresolved\", \"How adropin enhances Notch activation mechanistically unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing NB-3 induction in both raphespinal axons and scar cells inhibits regeneration revealed a context-dependent, growth-inhibitory role after CNS injury.\",\n      \"evidence\": \"Spinal cord transection with cell-type-specific NB-3 loss-of-function, synapse reformation, and electrophysiology\",\n      \"pmids\": [\"30156464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating the inhibitory signal not identified\", \"Relationship to NB-3's developmental pro-growth roles unreconciled\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Endothelial conditional knockout established a non-neuronal role: NB-3 maintains blood-brain barrier integrity through Notch-dependent control of tight junctions.\",\n      \"evidence\": \"Endothelial-specific NB-3 cKO, BBB permeability assays, tight-junction immunoblotting, transcriptomics, and Notch inhibition in vitro\",\n      \"pmids\": [\"35584741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Notch ligand-receptor engagement in endothelium not demonstrated\", \"Link between NB-3 Notch signaling and VEGF/VEGFR2 suppression mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Human cerebral organoid work implicated CNTN6 in radial glial fate, PAX6 nuclear-cytoplasmic localization, and lumenization, extending its Notch-linked role to early human cortical development.\",\n      \"evidence\": \"iPSC-derived cerebral organoids with CRISPR editing, radial glial marker and PAX6 immunofluorescence, and Notch pathway analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.09.681391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Mechanism connecting CNTN6 to PAX6 translocation undefined\", \"Human relevance not validated in vivo\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the direct receptor(s) mediating NB-3 homophilic and heterophilic signaling across its diverse roles, and the structural basis of its Notch1 and adropin interactions, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of NB-3 in complex with Notch1, adropin, CHL1, or PTP\\u03b1\", \"How a single GPI-anchored adhesion molecule switches between pro-growth and growth-inhibitory outputs is unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0007219\", \"supporting_discovery_ids\": [0, 8, 10]}\n    ],\n    \"complexes\": [\n      \"CHL1\\u2013NB-3\\u2013PTP\\u03b1 signaling complex\"\n    ],\n    \"partners\": [\n      \"CHL1\",\n      \"PTPRA\",\n      \"NOTCH1\",\n      \"DTX1\",\n      \"ENHO\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}