{"gene":"CBLN2","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2011,"finding":"Cbln2 specifically binds to α and β isoforms of neurexin carrying the splice site 4 insert [NRXs(S4+)] and induces synaptogenesis in cerebellar, hippocampal and cortical neurons in vitro. This binding is insensitive to extracellular Ca2+ concentrations.","method":"In vitro synaptogenesis assay, binding assay, competition with neuroligin 1","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding and functional synaptogenesis assay, replicated across multiple neuron types","pmids":["21410790"],"is_preprint":false},{"year":2007,"finding":"Cbln2 is secreted as an N-linked glycoprotein and can form not only homomeric but also heteromeric complexes with other Cbln family members (Cbln1, Cbln3, Cbln4) in vitro; heteromer formation modulates trafficking and secretion.","method":"Mammalian heterologous cell expression, co-immunoprecipitation, secretion assays","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods in a single study demonstrating secretion, glycosylation, and complex formation","pmids":["17331201"],"is_preprint":false},{"year":2012,"finding":"Cbln2 binds directly to the N-terminal domain of GluRδ1 (glutamate receptor δ1) and mediates preferentially inhibitory presynaptic differentiation of cultured cortical neurons via neurexins containing splice segment 4. Synaptogenic activity of Cbln2 is suppressed by the extracellular domain of NRXN1α or NRXN1β(S4+).","method":"HEK293T cell coculture synaptogenesis assay, direct binding assay, receptor-ligand competition","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding and functional synaptogenesis assays with receptor competition and domain mapping","pmids":["22191730"],"is_preprint":false},{"year":2011,"finding":"Cbln2 shows robust binding to NRXN1α and β-NRXNs selectively for splice segment 4-containing variants, and induces presynaptic differentiation of cortical neurons; surface plasmon resonance reveals Cbln2 has lower affinity for neurexins than Cbln1.","method":"Surface plasmon resonance, synaptogenesis assay with cortical neurons, binding competition","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — quantitative binding kinetics by SPR with functional synaptogenesis assay","pmids":["21356198"],"is_preprint":false},{"year":2012,"finding":"Cbln2 binds to GluRδ2 and neurexins 1-3, similar to Cbln1. Ectopic expression of Cbln2 in Purkinje cells of Cbln1-null mice rescues cerebellar deficits, demonstrating functional redundancy mediated by shared receptor binding properties.","method":"Transgenic mouse rescue experiment, binding assay, Cbln2 knockout mouse generation","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic rescue combined with binding assays across multiple receptor targets","pmids":["22117778"],"is_preprint":false},{"year":2018,"finding":"GluD1 (δ1 glutamate receptor) requires Cbln2 to assemble and maintain hippocampal excitatory synapses; GluD1 synaptic actions are absent in Cbln2 knockout mice. The mechanism involves a tripartite complex: Cbln2 bridges postsynaptic GluD1 and presynaptic neurexin 1β carrying splice site 4 insert (+S4).","method":"Cbln2 knockout mouse electrophysiology, genetic epistasis, loss-of-function with defined synaptic phenotype","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with electrophysiological phenotype and defined molecular complex","pmids":["29784783"],"is_preprint":false},{"year":2018,"finding":"Cbln1/Cbln2 double knockout mice display a selective ~50% decrease in hippocampal synapse density in stratum lacunosum moleculare of CA1 and dentate gyrus in 6-month-old mice, and similar decreases in striatum and retrosplenial cortex, demonstrating that Cbln2 contributes to long-term synapse maintenance rather than initial formation.","method":"Constitutive single, double, and triple KO mice; quantitative synapse density analysis; behavioral testing","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple KO combinations with quantitative synaptic phenotype, replicated across brain regions","pmids":["29691328"],"is_preprint":false},{"year":2022,"finding":"At CA1→subiculum synapses, Cbln2 mediates neurexin-1(SS4+)-dependent enhancement of NMDA receptors and neurexin-3(SS4+)-dependent suppression of AMPA receptors via GluD1, without affecting synapse formation or spine numbers. In the prefrontal cortex, Nrxn1SS4+-Cbln2 signaling selectively controls NMDA receptors.","method":"Constitutive Cbln2 KO in mice, electrophysiology at defined synapses, circuit-specific analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — circuit-specific electrophysiology in KO mice with multiple neurexin isoform dissection","pmids":["36205393"],"is_preprint":false},{"year":2021,"finding":"Cbln2 KO mice display compulsive behaviors including stereotypic pattern running, marble burying, explosive jumping, and excessive nest building, accompanied by decreased brain serotonin levels. Conditional deletion of Cbln2 from dorsal raphe neurons or presynaptic neurons synapsing onto dorsal raphe neurons reproduced compulsive behaviors. Injection of recombinant Cbln2 protein into dorsal raphe reversed compulsive behaviors.","method":"Constitutive and conditional KO mice, recombinant protein injection, pharmacological rescue with 5-HTP and fluoxetine","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic approaches (constitutive KO, conditional KO) plus protein rescue with defined behavioral phenotypes","pmids":["34158618"],"is_preprint":false},{"year":2021,"finding":"Hominini-specific deletions containing SOX5-binding sites within a retinoic acid-responsive CBLN2 enhancer drive transient PFC-enriched, laminar-specific upregulation of CBLN2 during midfetal development. In situ genetic humanization of the mouse Cbln2 enhancer increases and ectopically expands laminar Cbln2 expression and promotes PFC dendritic spine formation.","method":"Comparative transcriptomics, enhancer humanization knock-in mouse, in situ hybridization, dendritic spine analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic humanization with quantitative spine phenotype and molecular regulatory mechanism","pmids":["34599306"],"is_preprint":false},{"year":2023,"finding":"CBLN2 promotes endothelial-mesenchymal transition (EndMT) in pulmonary hypertension by activating the NF-κB/HIF-1α/Twist1 pathway; CBLN2 siRNA, NF-κB inhibitor PDTC, or HIF-1α inhibitor KC7F2 each inhibited hypoxia-induced EndMT.","method":"Hypoxia-induced rat PH model, siRNA knockdown, pharmacological inhibition, endothelial/mesenchymal marker immunostaining","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 3 — siRNA knockdown with pathway inhibitors in a cell/animal model, single lab","pmids":["37355224"],"is_preprint":false},{"year":2024,"finding":"A GRID1 variant at the Cbln2/Cbln4 interaction site in the distal amino terminal domain disrupts complex formation between GluD1 and Cbln2, demonstrating that this domain mediates the GluD1-Cbln2 interaction required for synapse organization.","method":"Biochemical co-immunoprecipitation, mutagenesis of human GRID1 variant, electrophysiology","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — domain-specific mutagenesis with biochemical complex disruption, single study","pmids":["37944084"],"is_preprint":false},{"year":2023,"finding":"Retinoic acid supplementation increases RARα binding to Cbln2 promoters (confirmed by ChIP assay), upregulates CBLN2 expression in cerebellum, and ameliorates motor incoordination in VPA-induced autism rat model, establishing an RARα-CBLN2 regulatory axis.","method":"ChIP assay for RARα binding to Cbln2 promoter, retinoic acid supplementation, motor behavior testing, Purkinje cell morphology","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrating direct transcriptional regulation combined with in vivo rescue, single lab","pmids":["37247722"],"is_preprint":false},{"year":2025,"finding":"SOX11 binds to 12 cis-regulatory elements within the Cbln2 promoter to enhance its transcription following spinal nerve ligation (SNL). siRNA knockdown of Sox11 or Cbln2 attenuated SNL-induced mechanical allodynia and thermal hyperalgesia. Exogenous CBLN2 activates NF-κB signaling and increases proinflammatory cytokines and neuronal hyperexcitability.","method":"ChIP for SOX11 binding, siRNA knockdown, intrathecal injection of recombinant CBLN2, electrophysiology, high-throughput sequencing","journal":"Neuroscience bulletin","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrating transcription factor binding, functional siRNA rescue, and downstream signaling assays; single lab","pmids":["41162740"],"is_preprint":false},{"year":2025,"finding":"TET3-mediated demethylation of the Cbln2 promoter drives upregulation of CBLN2 in trigeminal ganglion neurons following partial infraorbital nerve transection. Exogenous CBLN2 potentiates neuronal excitability and activates ERK signaling; MEK inhibition abolished CBLN2-induced hypersensitivity and suppressed proinflammatory cytokines.","method":"Methylation-specific PCR, bisulfite sequencing, Tet3 siRNA knockdown, patch-clamp electrophysiology, pharmacological MEK inhibition","journal":"The journal of headache and pain","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (epigenetic, electrophysiological, pharmacological) in single lab","pmids":["40665237"],"is_preprint":false},{"year":2018,"finding":"Novel peptides derived from CBLN2 precursor protein are identified in mouse spinal cord dorsal horn by mass spectrometry, and intrathecal injection of two of three CBLN2-derived peptides induced mechanical hypersensitivity in mice.","method":"Mass spectrometry, intrathecal injection, von Frey testing","journal":"Neuropeptides","confidence":"Medium","confidence_rationale":"Tier 3 — mass spectrometry identification combined with functional in vivo injection, single lab","pmids":["29705514"],"is_preprint":false},{"year":2024,"finding":"CBLN2 overexpression inhibits STAT3-induced PD-L1 and beta-catenin activation in colorectal cancer cells, suppresses oncogenic cell properties in vitro and tumor growth in vivo, and improves immune checkpoint blockade efficiency.","method":"Overexpression in CRC cell lines, in vivo tumor model, immunological assays","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, cancer cell line context inconsistent with primary neuronal function, limited mechanistic depth","pmids":["39577217"],"is_preprint":false},{"year":2017,"finding":"Using knockin reporter mice for Cbln2, Cbln2 is expressed in specific subsets of neurons (not all neurons): broadly in largely non-overlapping subpopulations of excitatory cortical neurons, selectively in inhibitory interneurons of the olfactory bulb, and at extremely high levels in the nucleus of the lateral olfactory tract.","method":"Knockin reporter mice, in situ hybridization, immunofluorescence","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic reporter knockin with systematic cell-type characterization","pmids":["28714144"],"is_preprint":false}],"current_model":"CBLN2 is a secreted glycoprotein that functions as a trans-synaptic organizer by forming tripartite complexes with presynaptic neurexins containing splice site 4 (especially Nrxn1β/3β SS4+) and postsynaptic GluD1/GluD2 receptors, thereby assembling and maintaining excitatory synapses in the hippocampus, prefrontal cortex, and other forebrain regions, differentially controlling NMDA- and AMPA-receptor responses in a circuit-specific manner; additionally, CBLN2 regulates serotonergic dorsal raphe circuits to suppress compulsive behaviors, its expression is transcriptionally controlled by retinoic acid/RARα and SOX11 (and epigenetically by TET3-mediated demethylation), and Hominini-specific enhancer changes drive increased CBLN2 expression to promote prefrontal cortical spinogenesis."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing that Cbln2 is a secreted glycoprotein that forms homo- and heteromeric complexes with other cerebellin family members resolved how CBLN family members are trafficked and made available in the extracellular space.","evidence":"Heterologous cell expression, co-immunoprecipitation, and secretion assays","pmids":["17331201"],"confidence":"High","gaps":["Stoichiometry and structural basis of heteromeric complexes undefined","In vivo significance of heteromer versus homomer formation unknown"]},{"year":2011,"claim":"Demonstrating that Cbln2 binds neurexins containing the SS4 insert and induces synaptogenesis across multiple neuron types established it as a trans-synaptic organizer with selectivity for a specific neurexin splice variant.","evidence":"In vitro synaptogenesis assays, binding assays with competition, and SPR kinetics across cerebellar, hippocampal, and cortical neurons","pmids":["21410790","21356198"],"confidence":"High","gaps":["Identity of the postsynaptic receptor partner not yet established in these studies","Lower affinity of Cbln2 versus Cbln1 for neurexins raises question of how Cbln2-specific synaptic functions arise"]},{"year":2012,"claim":"Identification of GluD1 and GluD2 as direct postsynaptic binding partners of Cbln2 completed the tripartite complex model (Neurexin–Cbln2–GluD) and showed functional redundancy with Cbln1 in cerebellar rescue experiments.","evidence":"Direct binding assays, HEK293T coculture synaptogenesis, transgenic Cbln1-null mouse rescue by ectopic Cbln2","pmids":["22191730","22117778"],"confidence":"High","gaps":["Whether Cbln2 has unique functions not shared with Cbln1 in endogenous circuits remained unclear","Structural determinants of GluD binding not resolved at residue level"]},{"year":2017,"claim":"Systematic cell-type mapping using knockin reporters revealed that Cbln2 is expressed in specific, largely non-overlapping subpopulations of excitatory cortical neurons and select inhibitory interneurons, defining the circuits in which it operates.","evidence":"Knockin reporter mice with in situ hybridization and immunofluorescence","pmids":["28714144"],"confidence":"Medium","gaps":["Functional significance of expression in specific subtypes (e.g., nucleus of the lateral olfactory tract) not tested","Developmental regulation of cell-type-specific expression not characterized"]},{"year":2018,"claim":"Genetic loss-of-function studies in Cbln2 knockout and Cbln1/2 double knockout mice established that Cbln2 is required for hippocampal synapse maintenance and for GluD1-dependent synaptic function via the Nrxn1β(SS4+)–Cbln2–GluD1 tripartite complex in vivo.","evidence":"Constitutive Cbln2 KO and double/triple KO mice with electrophysiology and quantitative synapse density analysis across brain regions","pmids":["29784783","29691328"],"confidence":"High","gaps":["Whether Cbln2 is required for initial synapse formation versus only maintenance debated","Downstream signaling from GluD1 upon Cbln2 binding not elucidated"]},{"year":2018,"claim":"Discovery of CBLN2-derived peptides in the spinal cord dorsal horn with pro-nociceptive activity revealed a potential non-synaptic-organizer function and a role in pain processing.","evidence":"Mass spectrometry identification from mouse spinal cord, intrathecal injection with von Frey testing","pmids":["29705514"],"confidence":"Medium","gaps":["Receptor mediating peptide-induced hypersensitivity not identified","Physiological relevance of processed peptides versus full-length Cbln2 unclear","Not independently replicated"]},{"year":2021,"claim":"Loss of Cbln2 in dorsal raphe circuits causes compulsive behaviors linked to decreased serotonin, establishing Cbln2 as a regulator of serotonergic circuit function and providing a direct link between trans-synaptic organization and behavioral output.","evidence":"Constitutive and conditional KO mice, recombinant Cbln2 protein injection rescue, pharmacological rescue with 5-HTP and fluoxetine","pmids":["34158618"],"confidence":"High","gaps":["Mechanism by which Cbln2 regulates serotonin levels (synapse number vs. receptor composition vs. other) not resolved","Human relevance for compulsive disorders not established"]},{"year":2021,"claim":"Hominini-specific deletions in a retinoic acid-responsive CBLN2 enhancer drive expanded prefrontal cortical expression and increased spinogenesis, establishing CBLN2 regulatory evolution as a contributor to human cortical connectivity.","evidence":"Comparative transcriptomics, enhancer humanization knock-in mouse with dendritic spine quantification","pmids":["34599306"],"confidence":"High","gaps":["Behavioral or cognitive consequences of humanized enhancer not tested","Whether spine increase reflects Cbln2's canonical tripartite complex mechanism unconfirmed"]},{"year":2022,"claim":"Circuit-specific electrophysiology revealed that Cbln2 differentially controls NMDA and AMPA receptor responses depending on neurexin isoform identity—Nrxn1(SS4+) enhances NMDA receptors while Nrxn3(SS4+) suppresses AMPA receptors—without affecting synapse number, dissecting synapse specification from synapse formation.","evidence":"Constitutive Cbln2 KO mice with electrophysiology at CA1→subiculum and prefrontal cortex synapses","pmids":["36205393"],"confidence":"High","gaps":["How Cbln2–GluD1 signaling differentially recruits NMDA versus AMPA receptors mechanistically unknown","Whether similar isoform-specific logic applies in other brain circuits untested"]},{"year":2023,"claim":"Transcriptional regulation of Cbln2 by RARα and SOX11, and epigenetic regulation by TET3-mediated promoter demethylation, were established in cerebellar and pain-related neural contexts, revealing upstream control mechanisms.","evidence":"ChIP assays for RARα and SOX11 binding to Cbln2 promoter regions, siRNA knockdown, methylation-specific PCR and bisulfite sequencing","pmids":["37247722","41162740","40665237"],"confidence":"Medium","gaps":["Whether RARα, SOX11, and TET3 regulation operates in the hippocampal and cortical circuits where Cbln2 synapse organization is best characterized","Interplay among these regulatory inputs not examined"]},{"year":2024,"claim":"A human GRID1 variant disrupting the Cbln2-binding interface of GluD1 confirmed that the distal amino-terminal domain of GluD1 mediates the functional GluD1–Cbln2 interaction.","evidence":"Mutagenesis of human GRID1 variant, co-immunoprecipitation, electrophysiology","pmids":["37944084"],"confidence":"Medium","gaps":["High-resolution structural model of GluD1–Cbln2 interface lacking","Whether this variant causes neurological disease in humans not established"]},{"year":null,"claim":"Key unresolved questions include how the Cbln2–GluD signaling complex differentially recruits NMDA versus AMPA receptors, what intracellular signaling cascades are activated downstream of GluD1/GluD2 upon Cbln2 binding, and whether Cbln2's roles in neuropathic pain and non-neuronal contexts reflect canonical or distinct molecular mechanisms.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the tripartite Neurexin–Cbln2–GluD complex exists","Downstream intracellular signaling from GluD upon Cbln2 engagement not defined","Mechanism by which Cbln2 regulates serotonin levels unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,5,7]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,5,6]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,0,8]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,5,6,7,8]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,2,5,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8]}],"complexes":["Neurexin–Cbln2–GluD tripartite complex","Cbln heteromeric complex (Cbln1/2/3/4)"],"partners":["NRXN1","NRXN3","GRID1","GRID2","CBLN1","CBLN3","CBLN4"],"other_free_text":[]},"mechanistic_narrative":"CBLN2 is a secreted glycoprotein that functions as a trans-synaptic organizer in the brain, bridging presynaptic neurexins and postsynaptic glutamate delta receptors to assemble, maintain, and functionally tune excitatory synapses. It is secreted as an N-linked glycoprotein capable of forming homomeric and heteromeric complexes with other cerebellin family members, and binds selectively to neurexins containing the splice site 4 insert (SS4+) and to GluD1/GluD2, forming a tripartite Neurexin–Cbln2–GluD complex that differentially controls NMDA- and AMPA-receptor responses in a circuit- and neurexin-isoform-specific manner [PMID:29784783, PMID:36205393, PMID:21410790]. Beyond forebrain synapse organization, Cbln2 regulates serotonergic dorsal raphe circuits, and its loss causes compulsive behaviors that are rescued by recombinant Cbln2 injection [PMID:34158618]. Hominini-specific enhancer changes drive expanded prefrontal cortical CBLN2 expression during midfetal development, promoting dendritic spine formation and contributing to human-specific cortical connectivity [PMID:34599306]."},"prefetch_data":{"uniprot":{"accession":"Q8IUK8","full_name":"Cerebellin-2","aliases":[],"length_aa":224,"mass_kda":24.1,"function":"Acts as a synaptic organizer in specific subsets of neurons in the brain. Essential for long-term maintenance but not establishment of excitatory synapses. Functions as part of a trans-synaptic complex by binding to postsynaptic GRID1 and presynaptic neurexins. This interaction helps regulate the activity of NMDA and AMPA receptors at hippocampal synapses without affecting synapse formation. NRXN1B-CBLN2-GRID1 complex transduce presynaptic signals into postsynaptic NMDAR response. NRXN3B-CBLN2-GRID1 complex transduce presynaptic signals into postsynaptic AMPAR response","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q8IUK8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CBLN2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CBLN2","total_profiled":1310},"omim":[{"mim_id":"615029","title":"PRECEREBELLIN 4; CBLN4","url":"https://www.omim.org/entry/615029"},{"mim_id":"612978","title":"PRECEREBELLIN 3; CBLN3","url":"https://www.omim.org/entry/612978"},{"mim_id":"600433","title":"PRECEREBELLIN 2; CBLN2","url":"https://www.omim.org/entry/600433"},{"mim_id":"600432","title":"PRECEREBELLIN 1; CBLN1","url":"https://www.omim.org/entry/600432"},{"mim_id":"178600","title":"PULMONARY HYPERTENSION, PRIMARY, 1; PPH1","url":"https://www.omim.org/entry/178600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Flagellar centriole","reliability":"Approved"},{"location":"Mid piece","reliability":"Approved"},{"location":"Principal piece","reliability":"Approved"},{"location":"Perinuclear theca","reliability":"Additional"},{"location":"Calyx","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":38.4}],"url":"https://www.proteinatlas.org/search/CBLN2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q8IUK8","domains":[{"cath_id":"2.60.120.40","chopping":"90-222","consensus_level":"high","plddt":93.6551,"start":90,"end":222}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IUK8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IUK8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IUK8-F1-predicted_aligned_error_v6.png","plddt_mean":75.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CBLN2","jax_strain_url":"https://www.jax.org/strain/search?query=CBLN2"},"sequence":{"accession":"Q8IUK8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IUK8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IUK8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IUK8"}},"corpus_meta":[{"pmid":"21410790","id":"PMC_21410790","title":"Cbln family 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This binding is insensitive to extracellular Ca2+ concentrations.\",\n      \"method\": \"In vitro synaptogenesis assay, binding assay, competition with neuroligin 1\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding and functional synaptogenesis assay, replicated across multiple neuron types\",\n      \"pmids\": [\"21410790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cbln2 is secreted as an N-linked glycoprotein and can form not only homomeric but also heteromeric complexes with other Cbln family members (Cbln1, Cbln3, Cbln4) in vitro; heteromer formation modulates trafficking and secretion.\",\n      \"method\": \"Mammalian heterologous cell expression, co-immunoprecipitation, secretion assays\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods in a single study demonstrating secretion, glycosylation, and complex formation\",\n      \"pmids\": [\"17331201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cbln2 binds directly to the N-terminal domain of GluRδ1 (glutamate receptor δ1) and mediates preferentially inhibitory presynaptic differentiation of cultured cortical neurons via neurexins containing splice segment 4. Synaptogenic activity of Cbln2 is suppressed by the extracellular domain of NRXN1α or NRXN1β(S4+).\",\n      \"method\": \"HEK293T cell coculture synaptogenesis assay, direct binding assay, receptor-ligand competition\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding and functional synaptogenesis assays with receptor competition and domain mapping\",\n      \"pmids\": [\"22191730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cbln2 shows robust binding to NRXN1α and β-NRXNs selectively for splice segment 4-containing variants, and induces presynaptic differentiation of cortical neurons; surface plasmon resonance reveals Cbln2 has lower affinity for neurexins than Cbln1.\",\n      \"method\": \"Surface plasmon resonance, synaptogenesis assay with cortical neurons, binding competition\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative binding kinetics by SPR with functional synaptogenesis assay\",\n      \"pmids\": [\"21356198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cbln2 binds to GluRδ2 and neurexins 1-3, similar to Cbln1. Ectopic expression of Cbln2 in Purkinje cells of Cbln1-null mice rescues cerebellar deficits, demonstrating functional redundancy mediated by shared receptor binding properties.\",\n      \"method\": \"Transgenic mouse rescue experiment, binding assay, Cbln2 knockout mouse generation\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic rescue combined with binding assays across multiple receptor targets\",\n      \"pmids\": [\"22117778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GluD1 (δ1 glutamate receptor) requires Cbln2 to assemble and maintain hippocampal excitatory synapses; GluD1 synaptic actions are absent in Cbln2 knockout mice. The mechanism involves a tripartite complex: Cbln2 bridges postsynaptic GluD1 and presynaptic neurexin 1β carrying splice site 4 insert (+S4).\",\n      \"method\": \"Cbln2 knockout mouse electrophysiology, genetic epistasis, loss-of-function with defined synaptic phenotype\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with electrophysiological phenotype and defined molecular complex\",\n      \"pmids\": [\"29784783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cbln1/Cbln2 double knockout mice display a selective ~50% decrease in hippocampal synapse density in stratum lacunosum moleculare of CA1 and dentate gyrus in 6-month-old mice, and similar decreases in striatum and retrosplenial cortex, demonstrating that Cbln2 contributes to long-term synapse maintenance rather than initial formation.\",\n      \"method\": \"Constitutive single, double, and triple KO mice; quantitative synapse density analysis; behavioral testing\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple KO combinations with quantitative synaptic phenotype, replicated across brain regions\",\n      \"pmids\": [\"29691328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"At CA1→subiculum synapses, Cbln2 mediates neurexin-1(SS4+)-dependent enhancement of NMDA receptors and neurexin-3(SS4+)-dependent suppression of AMPA receptors via GluD1, without affecting synapse formation or spine numbers. In the prefrontal cortex, Nrxn1SS4+-Cbln2 signaling selectively controls NMDA receptors.\",\n      \"method\": \"Constitutive Cbln2 KO in mice, electrophysiology at defined synapses, circuit-specific analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — circuit-specific electrophysiology in KO mice with multiple neurexin isoform dissection\",\n      \"pmids\": [\"36205393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cbln2 KO mice display compulsive behaviors including stereotypic pattern running, marble burying, explosive jumping, and excessive nest building, accompanied by decreased brain serotonin levels. Conditional deletion of Cbln2 from dorsal raphe neurons or presynaptic neurons synapsing onto dorsal raphe neurons reproduced compulsive behaviors. Injection of recombinant Cbln2 protein into dorsal raphe reversed compulsive behaviors.\",\n      \"method\": \"Constitutive and conditional KO mice, recombinant protein injection, pharmacological rescue with 5-HTP and fluoxetine\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic approaches (constitutive KO, conditional KO) plus protein rescue with defined behavioral phenotypes\",\n      \"pmids\": [\"34158618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hominini-specific deletions containing SOX5-binding sites within a retinoic acid-responsive CBLN2 enhancer drive transient PFC-enriched, laminar-specific upregulation of CBLN2 during midfetal development. In situ genetic humanization of the mouse Cbln2 enhancer increases and ectopically expands laminar Cbln2 expression and promotes PFC dendritic spine formation.\",\n      \"method\": \"Comparative transcriptomics, enhancer humanization knock-in mouse, in situ hybridization, dendritic spine analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic humanization with quantitative spine phenotype and molecular regulatory mechanism\",\n      \"pmids\": [\"34599306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CBLN2 promotes endothelial-mesenchymal transition (EndMT) in pulmonary hypertension by activating the NF-κB/HIF-1α/Twist1 pathway; CBLN2 siRNA, NF-κB inhibitor PDTC, or HIF-1α inhibitor KC7F2 each inhibited hypoxia-induced EndMT.\",\n      \"method\": \"Hypoxia-induced rat PH model, siRNA knockdown, pharmacological inhibition, endothelial/mesenchymal marker immunostaining\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — siRNA knockdown with pathway inhibitors in a cell/animal model, single lab\",\n      \"pmids\": [\"37355224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A GRID1 variant at the Cbln2/Cbln4 interaction site in the distal amino terminal domain disrupts complex formation between GluD1 and Cbln2, demonstrating that this domain mediates the GluD1-Cbln2 interaction required for synapse organization.\",\n      \"method\": \"Biochemical co-immunoprecipitation, mutagenesis of human GRID1 variant, electrophysiology\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific mutagenesis with biochemical complex disruption, single study\",\n      \"pmids\": [\"37944084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Retinoic acid supplementation increases RARα binding to Cbln2 promoters (confirmed by ChIP assay), upregulates CBLN2 expression in cerebellum, and ameliorates motor incoordination in VPA-induced autism rat model, establishing an RARα-CBLN2 regulatory axis.\",\n      \"method\": \"ChIP assay for RARα binding to Cbln2 promoter, retinoic acid supplementation, motor behavior testing, Purkinje cell morphology\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating direct transcriptional regulation combined with in vivo rescue, single lab\",\n      \"pmids\": [\"37247722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SOX11 binds to 12 cis-regulatory elements within the Cbln2 promoter to enhance its transcription following spinal nerve ligation (SNL). siRNA knockdown of Sox11 or Cbln2 attenuated SNL-induced mechanical allodynia and thermal hyperalgesia. Exogenous CBLN2 activates NF-κB signaling and increases proinflammatory cytokines and neuronal hyperexcitability.\",\n      \"method\": \"ChIP for SOX11 binding, siRNA knockdown, intrathecal injection of recombinant CBLN2, electrophysiology, high-throughput sequencing\",\n      \"journal\": \"Neuroscience bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating transcription factor binding, functional siRNA rescue, and downstream signaling assays; single lab\",\n      \"pmids\": [\"41162740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TET3-mediated demethylation of the Cbln2 promoter drives upregulation of CBLN2 in trigeminal ganglion neurons following partial infraorbital nerve transection. Exogenous CBLN2 potentiates neuronal excitability and activates ERK signaling; MEK inhibition abolished CBLN2-induced hypersensitivity and suppressed proinflammatory cytokines.\",\n      \"method\": \"Methylation-specific PCR, bisulfite sequencing, Tet3 siRNA knockdown, patch-clamp electrophysiology, pharmacological MEK inhibition\",\n      \"journal\": \"The journal of headache and pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (epigenetic, electrophysiological, pharmacological) in single lab\",\n      \"pmids\": [\"40665237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Novel peptides derived from CBLN2 precursor protein are identified in mouse spinal cord dorsal horn by mass spectrometry, and intrathecal injection of two of three CBLN2-derived peptides induced mechanical hypersensitivity in mice.\",\n      \"method\": \"Mass spectrometry, intrathecal injection, von Frey testing\",\n      \"journal\": \"Neuropeptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mass spectrometry identification combined with functional in vivo injection, single lab\",\n      \"pmids\": [\"29705514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CBLN2 overexpression inhibits STAT3-induced PD-L1 and beta-catenin activation in colorectal cancer cells, suppresses oncogenic cell properties in vitro and tumor growth in vivo, and improves immune checkpoint blockade efficiency.\",\n      \"method\": \"Overexpression in CRC cell lines, in vivo tumor model, immunological assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, cancer cell line context inconsistent with primary neuronal function, limited mechanistic depth\",\n      \"pmids\": [\"39577217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Using knockin reporter mice for Cbln2, Cbln2 is expressed in specific subsets of neurons (not all neurons): broadly in largely non-overlapping subpopulations of excitatory cortical neurons, selectively in inhibitory interneurons of the olfactory bulb, and at extremely high levels in the nucleus of the lateral olfactory tract.\",\n      \"method\": \"Knockin reporter mice, in situ hybridization, immunofluorescence\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic reporter knockin with systematic cell-type characterization\",\n      \"pmids\": [\"28714144\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CBLN2 is a secreted glycoprotein that functions as a trans-synaptic organizer by forming tripartite complexes with presynaptic neurexins containing splice site 4 (especially Nrxn1β/3β SS4+) and postsynaptic GluD1/GluD2 receptors, thereby assembling and maintaining excitatory synapses in the hippocampus, prefrontal cortex, and other forebrain regions, differentially controlling NMDA- and AMPA-receptor responses in a circuit-specific manner; additionally, CBLN2 regulates serotonergic dorsal raphe circuits to suppress compulsive behaviors, its expression is transcriptionally controlled by retinoic acid/RARα and SOX11 (and epigenetically by TET3-mediated demethylation), and Hominini-specific enhancer changes drive increased CBLN2 expression to promote prefrontal cortical spinogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CBLN2 is a secreted glycoprotein that functions as a trans-synaptic organizer in the brain, bridging presynaptic neurexins and postsynaptic glutamate delta receptors to assemble, maintain, and functionally tune excitatory synapses. It is secreted as an N-linked glycoprotein capable of forming homomeric and heteromeric complexes with other cerebellin family members, and binds selectively to neurexins containing the splice site 4 insert (SS4+) and to GluD1/GluD2, forming a tripartite Neurexin–Cbln2–GluD complex that differentially controls NMDA- and AMPA-receptor responses in a circuit- and neurexin-isoform-specific manner [PMID:29784783, PMID:36205393, PMID:21410790]. Beyond forebrain synapse organization, Cbln2 regulates serotonergic dorsal raphe circuits, and its loss causes compulsive behaviors that are rescued by recombinant Cbln2 injection [PMID:34158618]. Hominini-specific enhancer changes drive expanded prefrontal cortical CBLN2 expression during midfetal development, promoting dendritic spine formation and contributing to human-specific cortical connectivity [PMID:34599306].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that Cbln2 is a secreted glycoprotein that forms homo- and heteromeric complexes with other cerebellin family members resolved how CBLN family members are trafficked and made available in the extracellular space.\",\n      \"evidence\": \"Heterologous cell expression, co-immunoprecipitation, and secretion assays\",\n      \"pmids\": [\"17331201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of heteromeric complexes undefined\", \"In vivo significance of heteromer versus homomer formation unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that Cbln2 binds neurexins containing the SS4 insert and induces synaptogenesis across multiple neuron types established it as a trans-synaptic organizer with selectivity for a specific neurexin splice variant.\",\n      \"evidence\": \"In vitro synaptogenesis assays, binding assays with competition, and SPR kinetics across cerebellar, hippocampal, and cortical neurons\",\n      \"pmids\": [\"21410790\", \"21356198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the postsynaptic receptor partner not yet established in these studies\", \"Lower affinity of Cbln2 versus Cbln1 for neurexins raises question of how Cbln2-specific synaptic functions arise\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of GluD1 and GluD2 as direct postsynaptic binding partners of Cbln2 completed the tripartite complex model (Neurexin–Cbln2–GluD) and showed functional redundancy with Cbln1 in cerebellar rescue experiments.\",\n      \"evidence\": \"Direct binding assays, HEK293T coculture synaptogenesis, transgenic Cbln1-null mouse rescue by ectopic Cbln2\",\n      \"pmids\": [\"22191730\", \"22117778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cbln2 has unique functions not shared with Cbln1 in endogenous circuits remained unclear\", \"Structural determinants of GluD binding not resolved at residue level\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Systematic cell-type mapping using knockin reporters revealed that Cbln2 is expressed in specific, largely non-overlapping subpopulations of excitatory cortical neurons and select inhibitory interneurons, defining the circuits in which it operates.\",\n      \"evidence\": \"Knockin reporter mice with in situ hybridization and immunofluorescence\",\n      \"pmids\": [\"28714144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of expression in specific subtypes (e.g., nucleus of the lateral olfactory tract) not tested\", \"Developmental regulation of cell-type-specific expression not characterized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genetic loss-of-function studies in Cbln2 knockout and Cbln1/2 double knockout mice established that Cbln2 is required for hippocampal synapse maintenance and for GluD1-dependent synaptic function via the Nrxn1β(SS4+)–Cbln2–GluD1 tripartite complex in vivo.\",\n      \"evidence\": \"Constitutive Cbln2 KO and double/triple KO mice with electrophysiology and quantitative synapse density analysis across brain regions\",\n      \"pmids\": [\"29784783\", \"29691328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cbln2 is required for initial synapse formation versus only maintenance debated\", \"Downstream signaling from GluD1 upon Cbln2 binding not elucidated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery of CBLN2-derived peptides in the spinal cord dorsal horn with pro-nociceptive activity revealed a potential non-synaptic-organizer function and a role in pain processing.\",\n      \"evidence\": \"Mass spectrometry identification from mouse spinal cord, intrathecal injection with von Frey testing\",\n      \"pmids\": [\"29705514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating peptide-induced hypersensitivity not identified\", \"Physiological relevance of processed peptides versus full-length Cbln2 unclear\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Loss of Cbln2 in dorsal raphe circuits causes compulsive behaviors linked to decreased serotonin, establishing Cbln2 as a regulator of serotonergic circuit function and providing a direct link between trans-synaptic organization and behavioral output.\",\n      \"evidence\": \"Constitutive and conditional KO mice, recombinant Cbln2 protein injection rescue, pharmacological rescue with 5-HTP and fluoxetine\",\n      \"pmids\": [\"34158618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Cbln2 regulates serotonin levels (synapse number vs. receptor composition vs. other) not resolved\", \"Human relevance for compulsive disorders not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Hominini-specific deletions in a retinoic acid-responsive CBLN2 enhancer drive expanded prefrontal cortical expression and increased spinogenesis, establishing CBLN2 regulatory evolution as a contributor to human cortical connectivity.\",\n      \"evidence\": \"Comparative transcriptomics, enhancer humanization knock-in mouse with dendritic spine quantification\",\n      \"pmids\": [\"34599306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Behavioral or cognitive consequences of humanized enhancer not tested\", \"Whether spine increase reflects Cbln2's canonical tripartite complex mechanism unconfirmed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Circuit-specific electrophysiology revealed that Cbln2 differentially controls NMDA and AMPA receptor responses depending on neurexin isoform identity—Nrxn1(SS4+) enhances NMDA receptors while Nrxn3(SS4+) suppresses AMPA receptors—without affecting synapse number, dissecting synapse specification from synapse formation.\",\n      \"evidence\": \"Constitutive Cbln2 KO mice with electrophysiology at CA1→subiculum and prefrontal cortex synapses\",\n      \"pmids\": [\"36205393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Cbln2–GluD1 signaling differentially recruits NMDA versus AMPA receptors mechanistically unknown\", \"Whether similar isoform-specific logic applies in other brain circuits untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Transcriptional regulation of Cbln2 by RARα and SOX11, and epigenetic regulation by TET3-mediated promoter demethylation, were established in cerebellar and pain-related neural contexts, revealing upstream control mechanisms.\",\n      \"evidence\": \"ChIP assays for RARα and SOX11 binding to Cbln2 promoter regions, siRNA knockdown, methylation-specific PCR and bisulfite sequencing\",\n      \"pmids\": [\"37247722\", \"41162740\", \"40665237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RARα, SOX11, and TET3 regulation operates in the hippocampal and cortical circuits where Cbln2 synapse organization is best characterized\", \"Interplay among these regulatory inputs not examined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A human GRID1 variant disrupting the Cbln2-binding interface of GluD1 confirmed that the distal amino-terminal domain of GluD1 mediates the functional GluD1–Cbln2 interaction.\",\n      \"evidence\": \"Mutagenesis of human GRID1 variant, co-immunoprecipitation, electrophysiology\",\n      \"pmids\": [\"37944084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"High-resolution structural model of GluD1–Cbln2 interface lacking\", \"Whether this variant causes neurological disease in humans not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how the Cbln2–GluD signaling complex differentially recruits NMDA versus AMPA receptors, what intracellular signaling cascades are activated downstream of GluD1/GluD2 upon Cbln2 binding, and whether Cbln2's roles in neuropathic pain and non-neuronal contexts reflect canonical or distinct molecular mechanisms.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the tripartite Neurexin–Cbln2–GluD complex exists\", \"Downstream intracellular signaling from GluD upon Cbln2 engagement not defined\", \"Mechanism by which Cbln2 regulates serotonin levels unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 5, 7]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 0, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0120274\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 5, 6, 7, 8]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 2, 5, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [\n      \"Neurexin–Cbln2–GluD tripartite complex\",\n      \"Cbln heteromeric complex (Cbln1/2/3/4)\"\n    ],\n    \"partners\": [\n      \"NRXN1\",\n      \"NRXN3\",\n      \"GRID1\",\n      \"GRID2\",\n      \"CBLN1\",\n      \"CBLN3\",\n      \"CBLN4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}