Affinage

NRXN3

Neurexin-3-beta · UniProt Q9HDB5

Length
637 aa
Mass
69.3 kDa
Annotated
2026-04-29
26 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NRXN3 encodes a presynaptic cell-adhesion molecule that organizes synapse assembly, maturation, and plasticity through isoform-specific trans-synaptic interactions. The splice variant Nrxn3(25b+) binds C1ql2 at mossy fiber–CA3 synapses to recruit synaptic vesicles and enable long-term potentiation downstream of the Bcl11b→C1ql2 transcriptional pathway (PMID:38358390), while Nrxn3 is independently required for ribbon-synapse maturation in sensory hair cells across vertebrate species (PMID:39254120). In a non-neuronal context, NRXN3 competitively blocks RSK1-dependent phosphorylation of caspase-3 at T152, thereby stabilizing caspase-3 and promoting GSDME-dependent pyroptosis and gemcitabine chemosensitivity in intrahepatic cholangiocarcinoma (PMID:40324630). Biallelic loss-of-function variants in NRXN3 cause an autosomal recessive neurodevelopmental disorder featuring developmental delay, movement abnormalities, and intellectual disability (PMID:36898513).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 Low

    Establishing that NRXN3 expression extends beyond the nervous system addressed whether this neurexin functions exclusively at neuronal synapses, revealing broad tissue expression with heart-specific splice variants.

    Evidence RT-PCR and splicing analysis across human tissues

    PMID:12379233

    Open questions at the time
    • No direct biochemical reconstitution of proposed dystroglycan interaction
    • Functional significance of cardiac isoforms not tested
    • No loss-of-function data in non-neuronal tissues
  2. 2013 Medium

    Identifying FoxQ1 as a direct transcriptional repressor of NRXN3 established the first upstream regulatory mechanism and linked NRXN3 to growth suppression in glioma, raising the question of whether NRXN3 acts as a tumor suppressor in brain tumors.

    Evidence ChIP and luciferase reporter in glioma cell lines with FoxQ1 knockdown/overexpression

    PMID:23383267

    Open questions at the time
    • Mechanism by which NRXN3 suppresses glioma proliferation and migration not defined
    • Single-lab finding in glioma cell lines
    • No in vivo tumor model
  3. 2020 Medium

    Demonstrating that ZNF582 directly activates NRXN3 transcription and that NRXN3 restoration rescues ZNF582-loss-driven metastasis defined a second transcriptional regulator and reinforced an anti-metastatic role for NRXN3 in cancer.

    Evidence ChIP-seq, luciferase, rescue experiments, and in vivo metastasis models in nasopharyngeal carcinoma

    PMID:33038291

    Open questions at the time
    • Whether NRXN3 exerts anti-metastatic effects through synaptic adhesion-like mechanisms or a distinct pathway is unknown
    • Downstream signaling from NRXN3 in epithelial cells undefined
  4. 2023 Medium

    Discovery that biallelic NRXN3 loss-of-function variants cause a Mendelian neurodevelopmental disorder established direct human disease causality and linked the phenotype to Nrxn3 knockout mouse models.

    Evidence Whole-exome sequencing with CRISPR-edited cell functional validation and mouse phenotype comparison

    PMID:36898513

    Open questions at the time
    • Only a small number of families reported
    • Relative contributions of α- and β-neurexin-3 isoforms to the human phenotype not resolved
    • Synaptic pathophysiology in patient neurons not characterized
  5. 2023 Medium

    Identification of circNrxn3 as a circular RNA that binds SAM68 and regulates Nrxn3 mRNA splicing revealed a cis-acting autoregulatory feedback loop and linked isoform control to reward-related behavior.

    Evidence RNA immunoprecipitation, RNA-seq after lentiviral shRNA knockdown in rat orbitofrontal cortex, sucrose self-administration assay

    PMID:38036039

    Open questions at the time
    • Whether SAM68 is the sole effector of circNrxn3-mediated splicing regulation is untested
    • Which specific Nrxn3 exons are critically controlled by this axis remains partially defined
    • Replication in independent cohorts or species needed
  6. 2024 High

    Conditional Nrxn3 deletion in dentate gyrus granule neurons and complementary non-binding C1ql2 mutant experiments resolved an isoform-specific trans-synaptic code: Nrxn3(25b+)–C1ql2 interaction is required for synaptic vesicle recruitment and LTP at mossy fiber–CA3 synapses.

    Evidence Conditional knockout, dominant-negative C1ql2 mutant, in vivo and in vitro electrophysiology, genetic epistasis in mouse

    PMID:38358390

    Open questions at the time
    • Structural basis of the Nrxn3(25b+)–C1ql2 interface not determined
    • Whether other Nrxn3 splice variants function at distinct synapse types is unknown
  7. 2024 High

    Demonstrating that Nrxn3 is essential for ribbon-synapse maturation in both mouse and zebrafish hair cells extended the gene's synaptic organizer role to a non-conventional synapse type and established cross-species conservation.

    Evidence Nrxn3 knockout in mouse and zebrafish with confocal imaging, patch-clamp electrophysiology of hair cells and afferent neurons, acoustic startle assay

    PMID:39254120

    Open questions at the time
    • Postsynaptic binding partner at hair cell ribbon synapses not identified
    • Mechanism by which Nrxn3 coordinates pre- and postsynaptic assembly at ribbons not defined
  8. 2025 High

    A genome-scale CRISPR screen uncovered a non-synaptic mechanism: NRXN3 competitively inhibits RSK1-mediated phosphorylation of caspase-3 at T152, preventing FBXO1-dependent caspase-3 degradation and thereby promoting pyroptosis and chemosensitivity in cholangiocarcinoma.

    Evidence CRISPR screen, IP-mass spectrometry, co-immunoprecipitation, in vitro phosphorylation assay, in vivo murine ICC models with RSK1 inhibitor rescue

    PMID:40324630

    Open questions at the time
    • Whether this RSK1-caspase-3 competition operates in other cancer types or normal tissues is unknown
    • Structural determinants of NRXN3–RSK1 binding not mapped
    • Relationship between synaptic and non-synaptic NRXN3 isoforms in this context unclear
  9. 2025 Medium

    Knockdown of Nrxn3 specifically in the central amygdala increased nociceptive responses and neuronal activation across the orofacial pain circuit, establishing a functional role for Nrxn3 in pain modulation at a defined brain locus.

    Evidence Stereotaxic shRNA infusion in rat central amygdala, tendon ligature model, von Frey testing, c-Fos immunostaining

    PMID:41466820

    Open questions at the time
    • Whether Nrxn3's anti-nociceptive effect operates through specific trans-synaptic partners in the amygdala is unknown
    • Single pain model and sensory modality tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of isoform-specific ligand recognition (e.g., Nrxn3(25b+)–C1ql2), identification of the postsynaptic binding partner at ribbon synapses, and whether the non-synaptic RSK1-competitive mechanism is broadly relevant in normal physiology or restricted to cancer contexts.
  • No high-resolution structure of any Nrxn3 complex
  • Postsynaptic partner at ribbon synapses unidentified
  • Integration of synaptic and non-synaptic NRXN3 functions into a unified model lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1500931 Cell-Cell communication 2 R-HSA-5357801 Programmed Cell Death 1
Partners
C1QL2CASP3NLGN1RSK1SAM68

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 NRXN3 is expressed not only in neurons but also in heart, lung, pancreas, placenta, liver, and kidney, with heart-specific splicing variants identified; cardiac NRXN3 isoforms were proposed to participate in a complex involving dystroglycan and extracellular matrix proteins involved in intercellular connections. RT-PCR, tissue expression profiling, characterization of alternative splicing variants Biochemical and biophysical research communications Low 12379233
2008 Nrxn3beta mRNA expression is upregulated in the globus pallidus of mice developing cocaine appetence, implicating NRXN3 as a synaptic adhesion molecule involved in synaptic plasticity in basal ganglia indirect pathways underlying reward-related learning. Quantitative in situ hybridization/mRNA quantification in mouse brain regions after cocaine exposure Neuroreport Low 18418251
2013 FoxQ1 directly binds to the NRXN3 promoter and suppresses its transcriptional activity, thereby downregulating NRXN3 expression; loss of FoxQ1 reduces glioma cell proliferation and migration, indicating NRXN3 acts downstream of FoxQ1 as a tumor suppressor. ChIP assay, luciferase reporter assay, stable FoxQ1 knockdown/overexpression, MTT proliferation assay, transwell migration assay PloS one Medium 23383267
2020 ZNF582 directly regulates the transcription of NRXN3 (and Nectin-3) by binding to their promoters; ZNF582 knockdown reduces NRXN3 expression and promotes NPC cell migration/invasion/metastasis, while NRXN3 restoration reverses the pro-metastatic effect of ZNF582 loss. ChIP-seq, ChIP-qPCR, luciferase assay, qRT-PCR, Western blot, in vitro migration/invasion assays, in vivo metastasis models, rescue experiments Cancer communications Medium 33038291
2021 circ_0001367 acts as a sponge for miR-431, which in turn represses NRXN3; the circ_0001367/miR-431/NRXN3 axis suppresses glioma cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Luciferase reporter assay, RNA immunoprecipitation (RIP), functional overexpression/knockdown assays, rescue experiments, in vivo xenograft Cell death & disease Medium 34035217
2023 circNrxn3, a circular RNA originating from an intron of Nrxn3, binds the splicing factor SAM68 (by RNA immunoprecipitation) and regulates splicing of Nrxn3 mRNA; circNrxn3 knockdown in the orbitofrontal cortex alters Nrxn3 splicing, upregulates learning/memory pathway genes, and enhances sucrose self-administration and motivation for reward. RNA immunoprecipitation (RIP), RNA sequencing, qPCR, in vivo lentiviral shRNA knockdown, sucrose self-administration behavioral assay Progress in neurobiology Medium 38036039
2023 Loss-of-function variants in NRXN3 (homozygous missense and compound heterozygous) cause a Mendelian neurodevelopmental disorder with developmental delay, movement disorder, intellectual disability, and behavioral problems, with phenotype resembling homozygous Nrxn3α/β knockout mice. Whole exome sequencing, CRISPR-edited cell lines for functional validation, in-silico analysis, phenotypic comparison with Nrxn3 knockout mouse model Gene Medium 36898513
2024 C1ql2 interacts directly with a specific splice variant of neurexin-3, Nrxn3(25b+), at mossy fiber-CA3 synapses; this C1ql2-Nrxn3(25b+) interaction is required for synaptic vesicle recruitment and long-term potentiation (LTP). Deletion of Nrxn3 in dentate gyrus granule neurons or expression of a non-binding C1ql2 mutant recapitulates mossy fiber-CA3 synaptic deficits, placing Nrxn3(25b+) downstream of the Bcl11b→C1ql2 transcriptional pathway. Conditional Nrxn3 knockout in dentate gyrus, non-binding C1ql2 mutant expression, electrophysiological LTP recordings in vivo and in vitro, synaptic vesicle recruitment assay, genetic epistasis eLife High 38358390
2024 Presynaptic Nrxn3 is essential for ribbon-synapse maturation in hair cells; loss of Nrxn3 in mice and zebrafish results in failure of pre- and postsynaptic pairing and a ~60% loss of intact ribbon synapses, dramatically reducing presynaptic calcium responses in hair cells and postsynaptic responses in afferent neurons. Nrxn3 knockout in mouse and zebrafish, confocal imaging of ribbon synapses, patch-clamp electrophysiology of hair cells and afferent neurons, acoustic startle behavioral assay Development (Cambridge, England) High 39254120
2025 NRXN3 competitively blocks caspase-3 binding to the kinase RSK1, thereby preventing RSK1-dependent phosphorylation of caspase-3 at T152; loss of this phosphorylation impairs caspase-3 interaction with the ubiquitin ligase component FBXO1, stabilizes caspase-3, and promotes caspase-3/GSDME-dependent pyroptosis and gemcitabine sensitivity in intrahepatic cholangiocarcinoma. Genome-scale CRISPR-Cas9 screen, IP-mass spectrometry, co-immunoprecipitation, RNA-seq, in vitro phosphorylation assay, in vivo murine ICC models, RSK1 inhibitor and caspase-3 activator rescue Journal of advanced research High 40324630
2025 NRXN3 and its ligand NLGN1 (neuroligin-1) form a complex in hippocampus; maternal separation stress downregulates NRXN3 and NLGN1 prior to observed synaptic plasticity changes and depression-related behaviors in rats, placing the NRXN3-NLGN1 complex upstream of hippocampal synaptic plasticity and stress-induced depression susceptibility. Rat maternal separation model, Western blot/qPCR of NRXN3 and NLGN1, dendritic spine/branch morphology analysis, behavioral depression tests Brain research Low 40286836
2025 Knockdown of Nrxn3 in the central amygdala of rats increases nociceptive orofacial pain responses and elevates c-Fos expression in the central amygdala, lateral parabrachial nucleus, trigeminal ganglia, and trigeminal nucleus caudalis, demonstrating that Nrxn3 in the central amygdala attenuates myofascial nociception by reducing neuronal activity in the orofacial pain pathway. Stereotaxic Nrxn3 shRNA infusion into central amygdala, tendon ligature pain model, von Frey testing, c-Fos immunostaining Neurobiology of pain Medium 41466820

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. PLoS genetics 205 19557197
2013 FoxQ1 promotes glioma cells proliferation and migration by regulating NRXN3 expression. PloS one 47 23383267
2018 Low expression of aging-related NRXN3 is associated with Alzheimer disease: A systematic review and meta-analysis. Medicine 38 29995770
2009 Association of a polymorphism in the NRXN3 gene with the degree of smoking in schizophrenia: a preliminary study. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 37 19658047
2011 Influence of genomic variation in FTO at 16q12.2, MC4R at 18q22 and NRXN3 at 14q31 genes on breast cancer risk. Molecular biology reports 36 21688152
2014 Association study of common polymorphisms in MSRA, TFAP2B, MC4R, NRXN3, PPARGC1A, TMEM18, SEC16B, HOXB5 and OLFM4 genes with obesity-related traits among Portuguese children. Journal of human genetics 34 24670271
2011 Implications of central obesity-related variants in LYPLAL1, NRXN3, MSRA, and TFAP2B on quantitative metabolic traits in adult Danes. PloS one 34 21674055
2021 Circ_0001367 inhibits glioma proliferation, migration and invasion by sponging miR-431 and thus regulating NRXN3. Cell death & disease 33 34035217
2010 Polymorphisms in NRXN3, TFAP2B, MSRA, LYPLAL1, FTO and MC4R and their effect on visceral fat area in the Japanese population. Journal of human genetics 32 20703240
2013 Association study of NRXN3 polymorphisms with schizophrenia and risperidone-induced bodyweight gain in Chinese Han population. Progress in neuro-psychopharmacology & biological psychiatry 30 23306218
2020 ZNF582 hypermethylation promotes metastasis of nasopharyngeal carcinoma by regulating the transcription of adhesion molecules Nectin-3 and NRXN3. Cancer communications (London, England) 29 33038291
2008 Nrxn3 upregulation in the globus pallidus of mice developing cocaine addiction. Neuroreport 25 18418251
2018 A rare exonic NRXN3 deletion segregating with neurodevelopmental and neuropsychiatric conditions in a three-generation Chinese family. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 24 30076746
2002 Identification and characterization of heart-specific splicing of human neurexin 3 mRNA (NRXN3). Biochemical and biophysical research communications 19 12379233
2023 NRXN3 mutations cause developmental delay, movement disorder, and behavioral problems: CRISPR edited cells based WES results. Gene 17 36898513
2024 Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway. eLife 13 38358390
2013 DNA pooling base genome-wide association study identifies variants at NRXN3 associated with delayed encephalopathy after acute carbon monoxide poisoning. PloS one 13 24265751
2012 Examining the association of NRXN3 SNPs with borderline personality disorder phenotypes in heroin dependent cases and socio-economically disadvantaged controls. Drug and alcohol dependence 9 23245376
2024 Presynaptic Nrxn3 is essential for ribbon-synapse maturation in hair cells. Development (Cambridge, England) 8 39254120
2023 Case Report-An Inherited Loss-of-Function NRXN3 Variant Potentially Causes a Neurodevelopmental Disorder with Autism Consistent with Previously Described 14q24.3-31.1 Deletions. Genes 6 37372397
2023 Orbitofrontal intronic circular RNA from Nrxn3 mediates reward learning and motivation for reward. Progress in neurobiology 5 38036039
2025 NRXN3 regulates pyroptosis in intrahepatic cholangiocarcinoma via mediating the phospho-dependent ubiquitination and degradation of caspase-3. Journal of advanced research 2 40324630
2024 Presynaptic Nrxn3 is essential for ribbon-synapse assembly in hair cells. bioRxiv : the preprint server for biology 2 38410471
2025 Nrxn3 reduces myofascial nociceptive pain. Neurobiology of pain (Cambridge, Mass.) 1 41466820
2026 Robo2-Nrxn3 Deficiency: A Molecular Hub Linking Excitation-Inhibition Imbalance to the Pathogenesis of Schizophrenia. Schizophrenia bulletin 0 41863359
2025 NRXN3-NLGN1 complex influences the development of depression induced by maternal separation in rats. Brain research 0 40286836