{"gene":"NRXN2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2011,"finding":"Truncating mutations in NRXN2 fail to promote synaptic differentiation in neuron coculture assays and fail to bind either of the established postsynaptic partners LRRTM2 or NLGN2 in cell binding assays, demonstrating that NRXN2 requires intact C-terminus for synaptogenic activity and postsynaptic ligand binding.","method":"Neuron coculture synaptic differentiation assay; cell binding assays with LRRTM2 and NLGN2","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal functional assays (coculture + binding) in a single study, but not independently replicated","pmids":["21424692"],"is_preprint":false},{"year":2015,"finding":"Nrxn2α knockout mice show reduced spontaneous transmitter release specifically at excitatory synapses in the neocortex, altered short-term facilitation, and reduced NMDAR-dependent decay times and NMDAR-mediated responses, while inhibitory transmission and synapse densities remain unchanged; combined Nrxn2α/Nrxn2β deletion produces similar excitatory deficits, indicating Nrxn2β has no major independent role in basic excitatory transmission.","method":"Patch-clamp electrophysiology (spontaneous EPSCs/IPSCs, NMDAR recordings, paired-pulse facilitation) in Nrxn2α KO and Nrxn2α/β double-KO neocortical slices","journal":"Frontiers in synaptic neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple electrophysiological paradigms in two independent KO mouse lines with rigorous controls, replicated across models within the study","pmids":["25745399"],"is_preprint":false},{"year":2013,"finding":"In a zebrafish SMA model, SMN deficiency causes down-regulation and altered alternative splicing of nrxn2a; knockdown of two distinct nrxn2a isoforms phenocopies SMN-deficient fish by significantly reducing motor axon excitability, placing nrxn2a downstream of SMN in motor neuron function.","method":"Transcriptome analysis of SMN-deficient zebrafish; morpholino knockdown of nrxn2a isoforms; live Ca2+ imaging of motor axon excitability","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via knockdown with functional readout (Ca2+ imaging), single lab but two orthogonal approaches","pmids":["24218366"],"is_preprint":false},{"year":2025,"finding":"IGF2BP3 promotes stability of NRXN2 mRNA in an m6A-dependent manner in AML cells; a specific m6A modification site on NRXN2 mRNA was identified, and mutation of this site (c.1770A>T) decreased m6A modification, reduced mRNA stability, and reduced IGF2BP3 enrichment on NRXN2 mRNA; IGF2BP3 overexpression-driven cell proliferation was reversed by co-expression of the NRXN2 m6A mutant.","method":"MeRIP (m6A-seq) and RNA immunoprecipitation-qPCR; NRXN2-mut transfection; proliferation and apoptosis assays in HL-60 cells","journal":"Turkish journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A site mutagenesis combined with RIP-qPCR and rescue experiment, single lab","pmids":["41263466"],"is_preprint":false},{"year":2020,"finding":"miR-873 directly targets NRXN2 3'UTR and exerts a 20–30% inhibitory effect on NRXN2 expression; a seed-region mutation in miR-873 alters this targeting, confirmed by dual-luciferase reporter assay and qPCR.","method":"Dual-luciferase reporter assay; qPCR in transfected SH-SY5Y cells","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (luciferase + qPCR) confirming miRNA-target relationship, single lab","pmids":["33262327"],"is_preprint":false},{"year":2019,"finding":"Deletion of Nrxn2α in mice induces atypical structural connectivity in socially relevant brain regions (amygdala, anterior cingulate cortex, orbitofrontal cortex, hippocampus), as shown by increased fractional anisotropy and axial diffusivity, and altered axonal orientation independent of cell density changes.","method":"Diffusion tensor MRI (9.4 T) combined with CLARITY immunolabeling and quantitative axonal/cellular analysis in Nrxn2α KO mice","journal":"Molecular autism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal in vivo imaging methods (DTI + CLARITY) within same subjects, single lab","pmids":["30858964"],"is_preprint":false},{"year":2025,"finding":"Zebrafish nrxn2 full-locus knockout mutants develop normally without gross neurodevelopmental defects but display severe anxiety-like behaviours (bottom-dwelling, repetitive freezing/seizure events) specifically emerging at juvenile-to-adult stages, demonstrating a paralog-specific role for nrxn2 in anxiety regulation distinct from nrxn1 (which affects social behaviour/aggression) and nrxn3.","method":"CRISPR/Cas9 knockout zebrafish lines (transmembrane to full-locus deletions); behavioural phenotyping (open/closed field, social, aggression assays)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, behavioural phenotype without molecular mechanism","pmids":[],"is_preprint":true}],"current_model":"NRXN2 is a presynaptic cell-adhesion molecule that promotes excitatory synaptic transmission and short-term plasticity (partially via transsynaptic regulation of NMDA receptors), binds postsynaptic ligands LRRTM2 and NLGN2 through its intact extracellular domain, and is subject to post-transcriptional regulation by SMN-dependent alternative splicing and by IGF2BP3-mediated m6A-dependent mRNA stabilization, while its 3'UTR is targeted and repressed by miR-873."},"narrative":{"mechanistic_narrative":"NRXN2 is a presynaptic cell-adhesion molecule that promotes excitatory synaptic transmission and short-term plasticity in the central nervous system [PMID:25745399]. Its synaptogenic activity depends on an intact extracellular C-terminus, through which it engages the postsynaptic ligands LRRTM2 and NLGN2; truncating mutations abolish both synaptic differentiation in coculture and postsynaptic ligand binding [PMID:21424692]. Loss of the Nrxn2α isoform in mice selectively reduces spontaneous transmitter release at excitatory but not inhibitory synapses, alters short-term facilitation, and diminishes NMDAR-mediated responses, indicating a transsynaptic role in shaping glutamatergic signaling, while the Nrxn2β isoform contributes no major independent role in basic excitatory transmission [PMID:25745399]. At the systems level, Nrxn2α deletion produces atypical structural connectivity in socially relevant brain regions [PMID:30858964]. NRXN2 expression is controlled post-transcriptionally on multiple axes: SMN-dependent alternative splicing regulates nrxn2a isoforms downstream of SMN in motor neuron excitability [PMID:24218366], IGF2BP3 stabilizes NRXN2 mRNA in an m6A-dependent manner at a defined modification site to drive proliferation in leukemia cells [PMID:41263466], and miR-873 directly represses NRXN2 via its 3'UTR [PMID:33262327].","teleology":[{"year":2011,"claim":"Established that NRXN2's synaptogenic function and postsynaptic ligand engagement require an intact extracellular C-terminus, defining the structural basis of its adhesion activity.","evidence":"Neuron coculture synaptic differentiation assay and cell binding assays with LRRTM2 and NLGN2 using truncating mutants","pmids":["21424692"],"confidence":"Medium","gaps":["Does not resolve which domain regions mediate each ligand interaction","Single study, not independently replicated","No in vivo confirmation of binding requirement"]},{"year":2013,"claim":"Placed nrxn2a downstream of SMN, showing that SMN deficiency alters nrxn2a splicing and expression to impair motor axon excitability, linking NRXN2 to motor neuron pathophysiology.","evidence":"Transcriptome analysis of SMN-deficient zebrafish, morpholino knockdown of nrxn2a isoforms, and live Ca2+ imaging of motor axons","pmids":["24218366"],"confidence":"Medium","gaps":["Morpholino knockdown lacks genetic confirmation","Mechanism connecting splicing change to excitability defect unresolved","Mammalian relevance untested"]},{"year":2015,"claim":"Defined NRXN2's physiological role as a presynaptic regulator selective for excitatory transmission and NMDAR responses, distinguishing isoform contributions.","evidence":"Patch-clamp electrophysiology across multiple paradigms in Nrxn2α KO and Nrxn2α/β double-KO neocortical slices","pmids":["25745399"],"confidence":"High","gaps":["Transsynaptic mechanism of NMDAR regulation not molecularly mapped","Restricted to neocortex","Postsynaptic partner mediating effects in vivo not identified"]},{"year":2019,"claim":"Connected synaptic-level NRXN2 loss to circuit-level structural connectivity changes in brain regions relevant to social behavior.","evidence":"Diffusion tensor MRI and CLARITY immunolabeling with axonal/cellular quantification in Nrxn2α KO mice","pmids":["30858964"],"confidence":"Medium","gaps":["Causal link between connectivity changes and behavior not established","Molecular basis of altered axonal orientation unknown","Single lab"]},{"year":2020,"claim":"Identified miR-873 as a direct post-transcriptional repressor of NRXN2 acting through its 3'UTR.","evidence":"Dual-luciferase reporter assay and qPCR with seed-region mutation in transfected SH-SY5Y cells","pmids":["33262327"],"confidence":"Medium","gaps":["Modest (20-30%) repression of uncertain physiological significance","No in vivo demonstration","Single lab"]},{"year":2025,"claim":"Revealed an m6A-dependent stabilization axis whereby IGF2BP3 binds and stabilizes NRXN2 mRNA at a defined site to support cancer cell proliferation.","evidence":"MeRIP/m6A-seq, RIP-qPCR, m6A-site mutagenesis (c.1770A>T), and proliferation/apoptosis rescue assays in HL-60 AML cells","pmids":["41263466"],"confidence":"Medium","gaps":["Functional role of NRXN2 protein itself in AML not defined","Single lab","Relevance outside leukemia unknown"]},{"year":null,"claim":"How NRXN2's synaptic adhesion functions translate into specific behavioral outcomes such as anxiety regulation remains mechanistically unresolved.","evidence":"CRISPR/Cas9 zebrafish full-locus knockouts show anxiety-like behaviors but no molecular mechanism (preprint)","pmids":[],"confidence":"Low","gaps":["Behavioral phenotype lacks molecular mechanism","Preprint, not peer-reviewed","Paralog-specific basis of anxiety role undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,4]}],"complexes":[],"partners":["LRRTM2","NLGN2","IGF2BP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P58401","full_name":"Neurexin-2-beta","aliases":["Neurexin II-beta"],"length_aa":666,"mass_kda":70.9,"function":"Neuronal cell surface protein that may be involved in cell recognition and cell adhesion","subcellular_location":"Presynaptic cell membrane","url":"https://www.uniprot.org/uniprotkb/P58401/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NRXN2","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NRXN2","total_profiled":1310},"omim":[{"mim_id":"621407","title":"SCHIZOPHRENIA 17; SCZD17","url":"https://www.omim.org/entry/621407"},{"mim_id":"615029","title":"PRECEREBELLIN 4; CBLN4","url":"https://www.omim.org/entry/615029"},{"mim_id":"612840","title":"LEUKOCYTE ADHESION DEFICIENCY, TYPE III; LAD3","url":"https://www.omim.org/entry/612840"},{"mim_id":"610421","title":"KH DOMAIN-CONTAINING, RNA-BINDING, SIGNAL TRANSDUCTION-ASSOCIATED PROTEIN 3; KHDRBS3","url":"https://www.omim.org/entry/610421"},{"mim_id":"609374","title":"CELL DIVISION CYCLE-ASSOCIATED PROTEIN 5; CDCA5","url":"https://www.omim.org/entry/609374"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":184.5}],"url":"https://www.proteinatlas.org/search/NRXN2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P58401","domains":[{"cath_id":"2.60.120.200","chopping":"91-204_242-291","consensus_level":"high","plddt":96.5646,"start":91,"end":291}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P58401","model_url":"https://alphafold.ebi.ac.uk/files/AF-P58401-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P58401-F1-predicted_aligned_error_v6.png","plddt_mean":61.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NRXN2","jax_strain_url":"https://www.jax.org/strain/search?query=NRXN2"},"sequence":{"accession":"P58401","fasta_url":"https://rest.uniprot.org/uniprotkb/P58401.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P58401/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P58401"}},"corpus_meta":[{"pmid":"21424692","id":"PMC_21424692","title":"Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia.","date":"2011","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21424692","citation_count":229,"is_preprint":false},{"pmid":"24218366","id":"PMC_24218366","title":"SMN deficiency alters Nrxn2 expression and splicing in zebrafish and mouse models of spinal muscular atrophy.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24218366","citation_count":67,"is_preprint":false},{"pmid":"25745399","id":"PMC_25745399","title":"Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors.","date":"2015","source":"Frontiers in synaptic neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25745399","citation_count":67,"is_preprint":false},{"pmid":"24405718","id":"PMC_24405718","title":"CpG sites associated with NRP1, NRXN2 and miR-29b-2 are hypomethylated in monocytes during ageing.","date":"2014","source":"Immunity & ageing : I & A","url":"https://pubmed.ncbi.nlm.nih.gov/24405718","citation_count":25,"is_preprint":false},{"pmid":"33262327","id":"PMC_33262327","title":"Autism-associated miR-873 regulates ARID1B, SHANK3 and NRXN2 involved in neurodevelopment.","date":"2020","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/33262327","citation_count":24,"is_preprint":false},{"pmid":"30858964","id":"PMC_30858964","title":"The within-subject application of diffusion tensor MRI and CLARITY reveals brain structural changes in Nrxn2 deletion mice.","date":"2019","source":"Molecular autism","url":"https://pubmed.ncbi.nlm.nih.gov/30858964","citation_count":13,"is_preprint":false},{"pmid":"34126933","id":"PMC_34126933","title":"A genetic interaction of NRXN2 with GABRE, SYT1 and CASK in migraine patients: a case-control study.","date":"2021","source":"The journal of headache and pain","url":"https://pubmed.ncbi.nlm.nih.gov/34126933","citation_count":6,"is_preprint":false},{"pmid":"34777568","id":"PMC_34777568","title":"NRXN2 Possesses a Tumor Suppressor Potential via Inhibiting the Growth of Thyroid Cancer Cells.","date":"2021","source":"Computational and mathematical methods in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34777568","citation_count":4,"is_preprint":false},{"pmid":"39748282","id":"PMC_39748282","title":"NRXN2 Homozygous Variant Identified in a Family with Global Developmental Delay, Severe Intellectual Disability, EEG Abnormalities and Speech Delay: A new Syndrome?","date":"2025","source":"Clinical EEG and neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39748282","citation_count":1,"is_preprint":false},{"pmid":"41263466","id":"PMC_41263466","title":"IGF2BP3 Promoted the Overproliferation of AML Cells via Stability of NRXN2 mRNA.","date":"2025","source":"Turkish journal of haematology : official journal of Turkish Society of Haematology","url":"https://pubmed.ncbi.nlm.nih.gov/41263466","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.19.688847","title":"A novel method to sort and enrich sensory neurons","date":"2025-11-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.19.688847","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.24.690344","title":"Modelling mental disorders in zebrafish. Neurexins severely modulate anxiety, social behaviours and aggression","date":"2025-11-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.24.690344","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8728,"output_tokens":1893,"usd":0.02729,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8768,"output_tokens":2367,"usd":0.051507,"stage2_stop_reason":"end_turn"},"total_usd":0.078797,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"Truncating mutations in NRXN2 fail to promote synaptic differentiation in neuron coculture assays and fail to bind either of the established postsynaptic partners LRRTM2 or NLGN2 in cell binding assays, demonstrating that NRXN2 requires intact C-terminus for synaptogenic activity and postsynaptic ligand binding.\",\n      \"method\": \"Neuron coculture synaptic differentiation assay; cell binding assays with LRRTM2 and NLGN2\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal functional assays (coculture + binding) in a single study, but not independently replicated\",\n      \"pmids\": [\"21424692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nrxn2α knockout mice show reduced spontaneous transmitter release specifically at excitatory synapses in the neocortex, altered short-term facilitation, and reduced NMDAR-dependent decay times and NMDAR-mediated responses, while inhibitory transmission and synapse densities remain unchanged; combined Nrxn2α/Nrxn2β deletion produces similar excitatory deficits, indicating Nrxn2β has no major independent role in basic excitatory transmission.\",\n      \"method\": \"Patch-clamp electrophysiology (spontaneous EPSCs/IPSCs, NMDAR recordings, paired-pulse facilitation) in Nrxn2α KO and Nrxn2α/β double-KO neocortical slices\",\n      \"journal\": \"Frontiers in synaptic neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple electrophysiological paradigms in two independent KO mouse lines with rigorous controls, replicated across models within the study\",\n      \"pmids\": [\"25745399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In a zebrafish SMA model, SMN deficiency causes down-regulation and altered alternative splicing of nrxn2a; knockdown of two distinct nrxn2a isoforms phenocopies SMN-deficient fish by significantly reducing motor axon excitability, placing nrxn2a downstream of SMN in motor neuron function.\",\n      \"method\": \"Transcriptome analysis of SMN-deficient zebrafish; morpholino knockdown of nrxn2a isoforms; live Ca2+ imaging of motor axon excitability\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via knockdown with functional readout (Ca2+ imaging), single lab but two orthogonal approaches\",\n      \"pmids\": [\"24218366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IGF2BP3 promotes stability of NRXN2 mRNA in an m6A-dependent manner in AML cells; a specific m6A modification site on NRXN2 mRNA was identified, and mutation of this site (c.1770A>T) decreased m6A modification, reduced mRNA stability, and reduced IGF2BP3 enrichment on NRXN2 mRNA; IGF2BP3 overexpression-driven cell proliferation was reversed by co-expression of the NRXN2 m6A mutant.\",\n      \"method\": \"MeRIP (m6A-seq) and RNA immunoprecipitation-qPCR; NRXN2-mut transfection; proliferation and apoptosis assays in HL-60 cells\",\n      \"journal\": \"Turkish journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A site mutagenesis combined with RIP-qPCR and rescue experiment, single lab\",\n      \"pmids\": [\"41263466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-873 directly targets NRXN2 3'UTR and exerts a 20–30% inhibitory effect on NRXN2 expression; a seed-region mutation in miR-873 alters this targeting, confirmed by dual-luciferase reporter assay and qPCR.\",\n      \"method\": \"Dual-luciferase reporter assay; qPCR in transfected SH-SY5Y cells\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (luciferase + qPCR) confirming miRNA-target relationship, single lab\",\n      \"pmids\": [\"33262327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Deletion of Nrxn2α in mice induces atypical structural connectivity in socially relevant brain regions (amygdala, anterior cingulate cortex, orbitofrontal cortex, hippocampus), as shown by increased fractional anisotropy and axial diffusivity, and altered axonal orientation independent of cell density changes.\",\n      \"method\": \"Diffusion tensor MRI (9.4 T) combined with CLARITY immunolabeling and quantitative axonal/cellular analysis in Nrxn2α KO mice\",\n      \"journal\": \"Molecular autism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal in vivo imaging methods (DTI + CLARITY) within same subjects, single lab\",\n      \"pmids\": [\"30858964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Zebrafish nrxn2 full-locus knockout mutants develop normally without gross neurodevelopmental defects but display severe anxiety-like behaviours (bottom-dwelling, repetitive freezing/seizure events) specifically emerging at juvenile-to-adult stages, demonstrating a paralog-specific role for nrxn2 in anxiety regulation distinct from nrxn1 (which affects social behaviour/aggression) and nrxn3.\",\n      \"method\": \"CRISPR/Cas9 knockout zebrafish lines (transmembrane to full-locus deletions); behavioural phenotyping (open/closed field, social, aggression assays)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, behavioural phenotype without molecular mechanism\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NRXN2 is a presynaptic cell-adhesion molecule that promotes excitatory synaptic transmission and short-term plasticity (partially via transsynaptic regulation of NMDA receptors), binds postsynaptic ligands LRRTM2 and NLGN2 through its intact extracellular domain, and is subject to post-transcriptional regulation by SMN-dependent alternative splicing and by IGF2BP3-mediated m6A-dependent mRNA stabilization, while its 3'UTR is targeted and repressed by miR-873.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NRXN2 is a presynaptic cell-adhesion molecule that promotes excitatory synaptic transmission and short-term plasticity in the central nervous system [#1]. Its synaptogenic activity depends on an intact extracellular C-terminus, through which it engages the postsynaptic ligands LRRTM2 and NLGN2; truncating mutations abolish both synaptic differentiation in coculture and postsynaptic ligand binding [#0]. Loss of the Nrxn2\\u03b1 isoform in mice selectively reduces spontaneous transmitter release at excitatory but not inhibitory synapses, alters short-term facilitation, and diminishes NMDAR-mediated responses, indicating a transsynaptic role in shaping glutamatergic signaling, while the Nrxn2\\u03b2 isoform contributes no major independent role in basic excitatory transmission [#1]. At the systems level, Nrxn2\\u03b1 deletion produces atypical structural connectivity in socially relevant brain regions [#5]. NRXN2 expression is controlled post-transcriptionally on multiple axes: SMN-dependent alternative splicing regulates nrxn2a isoforms downstream of SMN in motor neuron excitability [#2], IGF2BP3 stabilizes NRXN2 mRNA in an m6A-dependent manner at a defined modification site to drive proliferation in leukemia cells [#3], and miR-873 directly represses NRXN2 via its 3'UTR [#4].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that NRXN2's synaptogenic function and postsynaptic ligand engagement require an intact extracellular C-terminus, defining the structural basis of its adhesion activity.\",\n      \"evidence\": \"Neuron coculture synaptic differentiation assay and cell binding assays with LRRTM2 and NLGN2 using truncating mutants\",\n      \"pmids\": [\"21424692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not resolve which domain regions mediate each ligand interaction\", \"Single study, not independently replicated\", \"No in vivo confirmation of binding requirement\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed nrxn2a downstream of SMN, showing that SMN deficiency alters nrxn2a splicing and expression to impair motor axon excitability, linking NRXN2 to motor neuron pathophysiology.\",\n      \"evidence\": \"Transcriptome analysis of SMN-deficient zebrafish, morpholino knockdown of nrxn2a isoforms, and live Ca2+ imaging of motor axons\",\n      \"pmids\": [\"24218366\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino knockdown lacks genetic confirmation\", \"Mechanism connecting splicing change to excitability defect unresolved\", \"Mammalian relevance untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined NRXN2's physiological role as a presynaptic regulator selective for excitatory transmission and NMDAR responses, distinguishing isoform contributions.\",\n      \"evidence\": \"Patch-clamp electrophysiology across multiple paradigms in Nrxn2\\u03b1 KO and Nrxn2\\u03b1/\\u03b2 double-KO neocortical slices\",\n      \"pmids\": [\"25745399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transsynaptic mechanism of NMDAR regulation not molecularly mapped\", \"Restricted to neocortex\", \"Postsynaptic partner mediating effects in vivo not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected synaptic-level NRXN2 loss to circuit-level structural connectivity changes in brain regions relevant to social behavior.\",\n      \"evidence\": \"Diffusion tensor MRI and CLARITY immunolabeling with axonal/cellular quantification in Nrxn2\\u03b1 KO mice\",\n      \"pmids\": [\"30858964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between connectivity changes and behavior not established\", \"Molecular basis of altered axonal orientation unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified miR-873 as a direct post-transcriptional repressor of NRXN2 acting through its 3'UTR.\",\n      \"evidence\": \"Dual-luciferase reporter assay and qPCR with seed-region mutation in transfected SH-SY5Y cells\",\n      \"pmids\": [\"33262327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Modest (20-30%) repression of uncertain physiological significance\", \"No in vivo demonstration\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed an m6A-dependent stabilization axis whereby IGF2BP3 binds and stabilizes NRXN2 mRNA at a defined site to support cancer cell proliferation.\",\n      \"evidence\": \"MeRIP/m6A-seq, RIP-qPCR, m6A-site mutagenesis (c.1770A>T), and proliferation/apoptosis rescue assays in HL-60 AML cells\",\n      \"pmids\": [\"41263466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of NRXN2 protein itself in AML not defined\", \"Single lab\", \"Relevance outside leukemia unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NRXN2's synaptic adhesion functions translate into specific behavioral outcomes such as anxiety regulation remains mechanistically unresolved.\",\n      \"evidence\": \"CRISPR/Cas9 zebrafish full-locus knockouts show anxiety-like behaviors but no molecular mechanism (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Behavioral phenotype lacks molecular mechanism\", \"Preprint, not peer-reviewed\", \"Paralog-specific basis of anxiety role undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LRRTM2\", \"NLGN2\", \"IGF2BP3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}