Affinage

CNTN6

Contactin-6 · UniProt Q9UQ52

Length
1028 aa
Mass
114.0 kDa
Annotated
2026-06-09
35 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 Medium

    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

    PMID:10717476

    Open questions at the time
    • Functional role of the splice isoform lacking Ig-domain residues 62–78 unresolved
    • No protein-level functional assignment from this study
  2. 2003 High

    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

    PMID:12884264

    Open questions at the time
    • Cellular/molecular basis of the motor phenotype not defined at this stage
    • Normal gross brain architecture left the mechanism unexplained
  3. 2004 Medium

    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

    PMID:15082708

    Open questions at the time
    • Direct receptor-ligand binding not structurally resolved
    • In vivo requirement for NB-3 in oligodendrogliogenesis not tested here
  4. 2007 High

    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

    PMID:18046458

    Open questions at the time
    • Downstream effectors linking PTPα activity to dendrite orientation not fully mapped
    • Whether Notch signaling intersects this complex unaddressed
  5. 2009 High

    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

    PMID:19672956

    Open questions at the time
    • Molecular partner mediating presynaptic function unknown
    • Causal link between synapse loss and cell death not dissected
  6. 2010 Medium

    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

    PMID:20176085

    Open questions at the time
    • Mechanism of excitatory selectivity unexplained
    • Functional/electrophysiological consequences not measured
  7. 2011 Medium

    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

    PMID:21622556

    Open questions at the time
    • Structural basis of the PTPα ectodomain–NB-3 interaction unknown
    • Whether trafficking control is required for the dendrite phenotype untested
  8. 2011 Medium

    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

    PMID:21817151

    Open questions at the time
    • Receptor mediating homophilic survival signaling not identified
    • Pathway linking NB-3 to ischemic protection undefined
  9. 2012 Medium

    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

    PMID:21935948

    Open questions at the time
    • Molecular guidance partners in CST axons unknown
    • Final trajectory is rescued by P21/P45, leaving the long-term consequence unclear
  10. 2014 Medium

    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

    PMID:25074942

    Open questions at the time
    • Structural basis of the adropin–NB-3 interaction unresolved
    • How adropin enhances Notch activation mechanistically unknown
  11. 2018 Medium

    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

    PMID:30156464

    Open questions at the time
    • Receptor mediating the inhibitory signal not identified
    • Relationship to NB-3's developmental pro-growth roles unreconciled
  12. 2022 Medium

    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

    PMID:35584741

    Open questions at the time
    • Direct Notch ligand-receptor engagement in endothelium not demonstrated
    • Link between NB-3 Notch signaling and VEGF/VEGFR2 suppression mechanistically incomplete
  13. 2025 Medium

    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)

    PMID:bio_10.1101_2025.10.09.681391

    Open questions at the time
    • Preprint, not peer-reviewed
    • Mechanism connecting CNTN6 to PAX6 translocation undefined
    • Human relevance not validated in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 2 GO:0098631 cell adhesion mediator activity 2 GO:0060089 molecular transducer activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 1
Partners
CHL1DTX1ENHONOTCH1PTPRA
Complex memberships
CHL1–NB-3–PTPα signaling complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 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. Cell-based signaling assays, nuclear translocation of NICD measured in primary cells, transcript analysis in primary oligodendrocytes The Journal of biological chemistry Medium 15082708
2007 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. Co-immunoprecipitation, NB-3-deficient mouse analysis showing misoriented apical dendrites, PTPα activity assays, genetic epistasis with PTPα knockout mice The EMBO journal High 18046458
2003 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. NB-3 knockout mouse generation (LacZ knockin), behavioral tests (rotarod, wire hang, horizontal rod-walking), brain histology Journal of neurobiology High 12884264
2009 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. Immunohistochemistry with synaptic markers (VGLUT1, mGluR1α), NB-3 knockout mouse analysis, quantification of synapse density and caspase-dependent death at postnatal time points Developmental neurobiology High 19672956
2010 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. Immunohistochemistry with vesicular transporter markers (VGLUT1, VGLUT2, VGAT), NB-3 knockout mouse quantification of synaptic puncta density Neuroscience letters Medium 20176085
2011 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. Co-expression in COS1 cells, PTPα knockout neuron analysis, subcellular fractionation, domain deletion mutants of PTPα The Journal of biological chemistry Medium 21622556
2012 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). 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 The Journal of comparative neurology Medium 21935948
2011 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. 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 Stroke Medium 21817151
2014 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. Yeast two-hybrid screening, adropin knockout mouse generation and behavioral/synaptic phenotyping, Notch target gene expression assays The Journal of biological chemistry Medium 25074942
2018 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. 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 of neurotrauma Medium 30156464
2022 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. Conditional endothelial NB-3 knockout mice, BBB permeability assays, tight junction protein immunoblotting, transcriptome sequencing, Notch pathway inhibition experiments in vitro Experimental neurology Medium 35584741
2000 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. Reporter gene analysis (promoter activity), RT-PCR and Northern blot for splice isoform identification, in situ hybridization, gene structure determination Gene Medium 10717476
2025 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. Human cerebral organoids, iPSC reprogramming, CRISPR/Cas9 genome editing, immunofluorescence for radial glial markers and PAX6 localization, Notch pathway analysis bioRxivpreprint Medium bio_10.1101_2025.10.09.681391

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 NB-3/Notch1 pathway via Deltex1 promotes neural progenitor cell differentiation into oligodendrocytes. The Journal of biological chemistry 122 15082708
2014 Adropin is a brain membrane-bound protein regulating physical activity via the NB-3/Notch signaling pathway in mice. The Journal of biological chemistry 108 25074942
2007 Neural recognition molecules CHL1 and NB-3 regulate apical dendrite orientation in the neocortex via PTP alpha. The EMBO journal 74 18046458
2003 Impaired motor coordination in mice lacking neural recognition molecule NB-3 of the contactin/F3 subgroup. Journal of neurobiology 62 12884264
2015 CNTN6 copy number variations in 14 patients: a possible candidate gene for neurodevelopmental and neuropsychiatric disorders. Journal of neurodevelopmental disorders 61 26257835
2016 CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders. Molecular psychiatry 58 27166760
2009 Contribution of the neural cell recognition molecule NB-3 to synapse formation between parallel fibers and Purkinje cells in mouse. Developmental neurobiology 57 19672956
2000 Expression and regulation of a gene encoding neural recognition molecule NB-3 of the contactin/F3 subgroup in mouse brain. Gene 50 10717476
2014 Single gene microdeletions and microduplication of 3p26.3 in three unrelated families: CNTN6 as a new candidate gene for intellectual disability. Molecular cytogenetics 46 25606055
2010 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. Neuroscience letters 28 20176085
2012 Loss of neural recognition molecule NB-3 delays the normal projection and terminal branching of developing corticospinal tract axons in the mouse. The Journal of comparative neurology 22 21935948
1998 cDNA cloning and chromosomal localization of neural adhesion molecule NB-3 in human. Journal of neuroscience research 22 9486763
2011 Loss of NB-3 aggravates cerebral ischemia by impairing neuron survival and neurite growth. Stroke 20 21817151
2018 Allele-Specific Biased Expression of the CNTN6 Gene in iPS Cell-Derived Neurons from a Patient with Intellectual Disability and 3p26.3 Microduplication Involving the CNTN6 Gene. Molecular neurobiology 19 29327201
2018 Cntn6 deficiency impairs allocentric navigation in mice. Brain and behavior 10 30106251
2018 Clinical and Molecular Characterization of Two Patients with CNTN6 Copy Number Variations. Cytogenetic and genome research 10 30508811
2011 Receptor-like protein-tyrosine phosphatase α enhances cell surface expression of neural adhesion molecule NB-3. The Journal of biological chemistry 10 21622556
2021 Familial Psychosis Associated With a Missense Mutation at MACF1 Gene Combined With the Rare Duplications DUP3p26.3 and DUP16q23.3, Affecting the CNTN6 and CDH13 Genes. Frontiers in genetics 8 33897758
2019 CNTN6 copy number variations: Uncertain clinical significance in individuals with neurodevelopmental disorders. European journal of medical genetics 8 30836150
2018 Schizophrenia and epilepsy as a result of maternally inherited CNTN6 copy number variant. Schizophrenia research 8 29983269
2019 Time origin and structural analysis of the induced CRISPR/cas9 megabase-sized deletions and duplications involving the Cntn6 gene in mice. Scientific reports 7 31578377
2022 NB-3 expression in endothelial cells contributes to the maintenance of blood brain barrier integrity in a mouse high-altitude cerebral edema model. Experimental neurology 6 35584741
2019 Decreased Expression of Synaptophysin 1 (SYP1 Major Synaptic Vesicle Protein p38) and Contactin 6 (CNTN6/NB3) in the Cerebellar Vermis of reln Haplodeficient Mice. Cellular and molecular neurobiology 4 31098770
2018 Induced NB-3 Limits Regenerative Potential of Serotonergic Axons after Complete Spinal Transection. Journal of neurotrauma 4 30156464
2025 Momentum-resolved fingerprint of Mottness in layer-dimerized Nb3Br8. Nature communications 2 40301319
2019 Generation of the induced pluripotent stem cell line, ICAGi002-A, from unaffected carrier megabase scaled duplication involving the CNTN6 gene. Stem cell research 2 31518906
2019 Stability, Crystal Chemistry, 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. Inorganic chemistry 1 31675217
2019 Generation of four iPSC lines from two siblings with a microdeletion at the CNTN6 gene and intellectual disability. Stem cell research 1 31678775
2016 [Estimation of association of CNTN6 copy number variation with idiopathic intellectual disability]. Genetika 1 29369566
2026 Realizing Highly Reversible Nb5+/Nb4+/Nb3+ Redox Reactions in Bulk NASICON-NaNbAl(PO4)3 Anode Under Higher Current Rates. Small (Weinheim an der Bergstrasse, Germany) 0 41636151
2026 Role of CNTN6 in neurodevelopment and neuropathology. Frontiers in neuroscience 0 42100732
2024 The effects of Sr-substitution in Ba2SmTi2Nb3O15 ceramics: structural study, optical properties, and complex impedance spectroscopy. RSC advances 0 38487518
2021 A15 Nb3Si: a 'high'Tcsuperconductor synthesized at a pressure of one megabar and metastable at ambient conditions. Journal of physics. Condensed matter : an Institute of Physics journal 0 33647891
2020 Nb3Sn multicell cavity coating system at Jefferson Lab. The Review of scientific instruments 0 32752803
2007 Nuclear spin relaxation and diffusion of hydrogen in the A15 compound Nb(3)AlH(x). Journal of physics. Condensed matter : an Institute of Physics journal 0 22049126

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