{"gene":"C1QL2","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2008,"finding":"CTRP10 (C1QL2) is a secreted glycoprotein that forms trimers as its basic structural unit, and trimers are further assembled into higher-order oligomeric complexes via disulfide bonding mediated by N-terminal cysteine residues.","method":"Heterologous mammalian cell expression, biochemical characterization (SDS-PAGE, size exclusion), mutagenesis of cysteine residues","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct biochemical characterization in heterologous cells with cysteine-mediated oligomerization demonstrated, single lab","pmids":["18783346"],"is_preprint":false},{"year":2010,"finding":"C1ql2 protein is secreted and forms both homomeric and heteromeric complexes, as well as hexameric and higher-order complexes via N-terminal cysteine residues, when expressed in heterologous cells.","method":"Heterologous cell expression, biochemical fractionation, co-immunoprecipitation","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical characterization with multiple complex forms demonstrated, single lab, two orthogonal methods","pmids":["20525073"],"is_preprint":false},{"year":2011,"finding":"CTRP13 forms heteromeric complexes with CTRP10 (C1QL2) when co-expressed; this heteromeric association does not involve conserved N-terminal Cys residues.","method":"Co-expression in heterologous cells, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mutagenesis distinguishing the interaction domain, single lab","pmids":["21378161"],"is_preprint":false},{"year":2013,"finding":"CTRP11 forms heteromeric complexes with CTRP10 (C1QL2) via C-terminal globular domains when co-expressed.","method":"Co-expression in heterologous cells, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct co-IP with domain mapping, single lab","pmids":["23449976"],"is_preprint":false},{"year":2015,"finding":"Crystal structures of the globular C1q-domain of C1QL2 reveal a trimeric arrangement with each protomer forming a jelly-roll fold of 10 β-strands; C1QL2 trimers contain four Ca2+-binding sites along the trimeric symmetry axis plus additional surface Ca2+-binding sites. Mutation of Ca2+-coordinating residues lowered Ca2+-binding affinity and protein stability.","method":"X-ray crystallography, site-directed mutagenesis, biophysical stability assays","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure combined with functional mutagenesis of Ca2+-binding residues","pmids":["25752542"],"is_preprint":false},{"year":2015,"finding":"C1QL1, C1QL2, and C1QL3 bind to brain-specific angiogenesis inhibitor 3 (BAI3), an adhesion-type GPCR implicated in dendritic morphology regulation via actin filament organization.","method":"Binding assay (structural study context, in vitro binding)","journal":"Structure (London, England : 1993)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding established in structural study context, single lab","pmids":["25752542"],"is_preprint":false},{"year":2016,"finding":"C1ql2 and C1ql3, produced by mossy fibers, serve as extracellular organizers that recruit functional postsynaptic kainate receptor (KAR) complexes at mossy fiber–CA3 synapses. C1ql2 specifically binds the amino-terminal domains of postsynaptic GluK2 and GluK4 KAR subunits and the presynaptic neurexin-3 containing exon 25b (splice site 5) in vitro. In C1ql2/3 double-null mice, CA3 synaptic responses lost the slow KAR-mediated components.","method":"In vitro binding assays (pulldown with recombinant proteins), genetic knockout mice, electrophysiology","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro binding with defined subunits, double-KO mouse electrophysiology confirming KAR loss-of-function, replicated across multiple orthogonal methods","pmids":["27133466"],"is_preprint":false},{"year":2024,"finding":"C1ql2 is a direct functional target of the transcription factor Bcl11b; Bcl11b regulates synaptic vesicle recruitment and long-term potentiation at mossy fiber–CA3 synapses through C1ql2. C1ql2 exerts its synaptic functions through direct interaction with neurexin-3 splice variant Nrxn3(25b+). Expression of a non-binding C1ql2 mutant or deletion of Nrxn3 in dentate gyrus granule neurons recapitulated the Bcl11b and C1ql2 mutant synaptic phenotypes.","method":"Genetic knockout/conditional deletion in mice, expression of non-binding mutant, in vivo and in vitro electrophysiology, molecular interaction assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — epistasis via genetic KO and rescue/dominant-negative, multiple orthogonal methods (KO, mutant expression, electrophysiology), rigorous controls","pmids":["38358390"],"is_preprint":false},{"year":2025,"finding":"CTRP10 (C1QL2) negatively regulates body weight in female mice in a sexually dimorphic manner. Female, but not male, Ctrp10 knockout mice develop obesity on a low-fat diet while maintaining largely preserved insulin sensitivity, glucose tolerance, and metabolic health (no steatosis, dyslipidemia, or inflammation), uncoupling obesity from metabolic dysfunction.","method":"Constitutive knockout mice, metabolic phenotyping (glucose tolerance, insulin tolerance, body composition, plasma lipids), multi-tissue transcriptomics","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — constitutive KO with comprehensive metabolic phenotyping across multiple tissues and parameters, published in peer-reviewed journal","pmids":["40126547"],"is_preprint":false},{"year":2026,"finding":"CTRP10 (C1QL2) is required for optimal motor function. Female Ctrp10 KO mice show impaired motor coordination (rotarod) and fine motor skills (beam walk, complex running wheel) with sex-biased effects. CTRP10 loss alters cerebellar and motor cortex pathways related to synaptic organization and mitochondrial respiration, and reduces mitochondrial respiration in the motor cortex.","method":"Constitutive knockout mice, behavioral testing (rotarod, beam walk, complex running wheel, grip strength), transcriptomic analysis, mitochondrial respiration assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — constitutive KO with multiple orthogonal behavioral and molecular readouts, functional mitochondrial assay, single lab","pmids":["41933728"],"is_preprint":false}],"current_model":"C1QL2/CTRP10 is a secreted C1q-family glycoprotein that forms trimers (and higher-order oligomers via N-terminal cysteine disulfide bonds) and functions as a transsynaptic organizer at hippocampal mossy fiber–CA3 synapses by binding presynaptic neurexin-3(25b+) and postsynaptic kainate receptor subunits GluK2/GluK4 to recruit functional KAR complexes, with its synaptic expression controlled by transcription factor Bcl11b; peripherally, CTRP10 negatively regulates female body weight, and its loss produces sex-biased motor coordination deficits accompanied by altered cerebellar/motor cortex gene expression and reduced mitochondrial respiration."},"narrative":{"mechanistic_narrative":"C1QL2 (CTRP10) is a secreted C1q-family glycoprotein that acts as a transsynaptic organizer in the brain and as a sex-biased peripheral regulator of body weight and motor function [PMID:27133466, PMID:40126547]. The protein assembles into trimers as its basic structural unit, with each protomer adopting a jelly-roll globular C1q fold; trimers coordinate multiple Ca2+ ions along their symmetry axis and are further assembled into hexameric and higher-order oligomers through disulfide bonds formed by N-terminal cysteine residues [PMID:18783346, PMID:25752542]. Beyond homo-oligomerization, C1QL2 forms heteromeric complexes with related CTRP proteins through distinct interfaces—via C-terminal globular domains in the case of CTRP11 and through a cysteine-independent interface with CTRP13 [PMID:21378161, PMID:23449976]. At hippocampal mossy fiber–CA3 synapses, C1QL2 produced by mossy fibers bridges the synaptic cleft by binding presynaptic neurexin-3 containing exon 25b and the amino-terminal domains of postsynaptic kainate receptor subunits GluK2 and GluK4, thereby recruiting functional KAR complexes; loss of C1ql2/3 abolishes the slow KAR-mediated synaptic response [PMID:27133466]. Its synaptic expression is a direct functional target of the transcription factor Bcl11b, and C1QL2 mediates Bcl11b-dependent synaptic vesicle recruitment and long-term potentiation through its interaction with Nrxn3(25b+) [PMID:38358390]. C1QL2 also binds the adhesion-type GPCR BAI3 [PMID:25752542]. Peripherally, C1QL2 negatively regulates female body weight, with Ctrp10 knockout females developing obesity uncoupled from metabolic dysfunction, and is required for optimal motor coordination, with its loss altering cerebellar and motor cortex synaptic and mitochondrial pathways and reducing motor cortex mitochondrial respiration [PMID:40126547, PMID:41933728].","teleology":[{"year":2008,"claim":"Established the basic structural architecture of the secreted protein, showing it builds from trimers into higher-order oligomers via N-terminal cysteine disulfide bonds.","evidence":"Heterologous mammalian cell expression with SDS-PAGE, size exclusion, and cysteine mutagenesis","pmids":["18783346"],"confidence":"Medium","gaps":["Functional consequence of oligomerization not addressed","No physiological binding partners identified"]},{"year":2010,"claim":"Confirmed secretion and extended the oligomerization model to include homomeric, heteromeric, and hexameric assemblies governed by N-terminal cysteines.","evidence":"Heterologous cell expression, biochemical fractionation, and co-immunoprecipitation","pmids":["20525073"],"confidence":"Medium","gaps":["Heteromeric partners not yet defined in this work","In vivo relevance of complexes untested"]},{"year":2011,"claim":"Identified CTRP13 as a heteromeric partner and showed this association uses an interface distinct from the conserved N-terminal cysteines, indicating multiple oligomerization modes.","evidence":"Co-expression in heterologous cells with co-immunoprecipitation and mutagenesis","pmids":["21378161"],"confidence":"Medium","gaps":["Physiological significance of the heteromer unknown","Single-lab co-IP without reciprocal in vivo validation"]},{"year":2013,"claim":"Mapped a second heteromeric partnership with CTRP11 to the C-terminal globular domains, defining domain-specific assembly rules for the family.","evidence":"Co-expression in heterologous cells with co-immunoprecipitation and domain mapping","pmids":["23449976"],"confidence":"Medium","gaps":["Functional output of the CTRP11 heteromer not established","No endogenous tissue confirmation"]},{"year":2015,"claim":"Resolved the atomic structure of the globular C1q domain and identified Ca2+-binding sites essential for protein stability, while also showing C1QL2 binds the adhesion-GPCR BAI3.","evidence":"X-ray crystallography, site-directed mutagenesis, biophysical stability assays, and in vitro binding","pmids":["25752542"],"confidence":"High","gaps":["Downstream signaling consequence of BAI3 binding not defined","Role of Ca2+ sites in receptor engagement untested"]},{"year":2016,"claim":"Defined C1QL2's core synaptic function as a transsynaptic organizer bridging presynaptic neurexin-3(25b+) and postsynaptic GluK2/GluK4 to recruit functional kainate receptors at mossy fiber–CA3 synapses.","evidence":"In vitro pulldown with recombinant proteins, C1ql2/3 double-knockout mice, and electrophysiology","pmids":["27133466"],"confidence":"High","gaps":["Stoichiometry of the transsynaptic complex unresolved","Contribution of oligomeric state to bridging unaddressed"]},{"year":2024,"claim":"Placed C1QL2 downstream of the transcription factor Bcl11b and demonstrated that its Nrxn3(25b+) interaction is required for synaptic vesicle recruitment and long-term potentiation, establishing a transcription-to-synapse axis.","evidence":"Conditional knockout and Nrxn3 deletion in mice, non-binding mutant expression, in vivo/in vitro electrophysiology, and interaction assays","pmids":["38358390"],"confidence":"High","gaps":["Other Bcl11b targets contributing to phenotype not excluded","Mechanism coupling KAR recruitment to LTP not fully detailed"]},{"year":2025,"claim":"Revealed a peripheral role: C1QL2 negatively regulates female body weight in a sexually dimorphic manner, uncoupling obesity from metabolic dysfunction.","evidence":"Constitutive knockout mice with comprehensive metabolic phenotyping and multi-tissue transcriptomics","pmids":["40126547"],"confidence":"High","gaps":["Tissue source and receptor mediating the metabolic effect unknown","Mechanistic basis of sexual dimorphism unresolved"]},{"year":2026,"claim":"Extended the loss-of-function phenotype to motor behavior, linking C1QL2 to cerebellar/motor cortex synaptic organization and mitochondrial respiration.","evidence":"Constitutive knockout mice, behavioral testing, transcriptomics, and mitochondrial respiration assays","pmids":["41933728"],"confidence":"High","gaps":["Direct molecular link between C1QL2 and mitochondrial respiration not established","Whether motor deficit is cell-autonomous to specific neuron types unknown"]},{"year":null,"claim":"How C1QL2's biochemical features—oligomeric state, Ca2+ coordination, and receptor binding—are integrated to produce both its central synaptic organizing function and its peripheral metabolic/motor roles remains unresolved.","evidence":"No single study connects the structural, synaptic, and peripheral findings mechanistically","pmids":[],"confidence":"Medium","gaps":["No unified receptor map across CNS and peripheral tissues","Mechanism of sex-biased peripheral action undefined","Functional relevance of CTRP heteromers in vivo untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[6,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,5]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,6]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[6]}],"complexes":[],"partners":["NRXN3","GRIK2","GRIK4","ADGRB3","C1QL3","CTRP11","CTRP13","BCL11B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z5L3","full_name":"Complement C1q-like protein 2","aliases":["C1q and tumor necrosis factor-related protein 10","C1q/TNF-related protein 10"],"length_aa":287,"mass_kda":29.5,"function":"May regulate the number of excitatory synapses that are formed on hippocampus neurons. Has no effect on inhibitory synapses (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q7Z5L3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C1QL2","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/C1QL2","total_profiled":1310},"omim":[{"mim_id":"615229","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 4; C1QL4","url":"https://www.omim.org/entry/615229"},{"mim_id":"615227","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 3; C1QL3","url":"https://www.omim.org/entry/615227"},{"mim_id":"615099","title":"ERYTHROFERRONE; ERFE","url":"https://www.omim.org/entry/615099"},{"mim_id":"614330","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 2; C1QL2","url":"https://www.omim.org/entry/614330"},{"mim_id":"611586","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 1; C1QL1","url":"https://www.omim.org/entry/611586"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":26.2}],"url":"https://www.proteinatlas.org/search/C1QL2"},"hgnc":{"alias_symbol":["CTRP10","C1QTNF10"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z5L3","domains":[{"cath_id":"2.60.120.40","chopping":"156-287","consensus_level":"medium","plddt":95.043,"start":156,"end":287}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z5L3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z5L3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z5L3-F1-predicted_aligned_error_v6.png","plddt_mean":74.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C1QL2","jax_strain_url":"https://www.jax.org/strain/search?query=C1QL2"},"sequence":{"accession":"Q7Z5L3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z5L3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z5L3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z5L3"}},"corpus_meta":[{"pmid":"18783346","id":"PMC_18783346","title":"Molecular, 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cysteine residues\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct biochemical characterization in heterologous cells with cysteine-mediated oligomerization demonstrated, single lab\",\n      \"pmids\": [\"18783346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C1ql2 protein is secreted and forms both homomeric and heteromeric complexes, as well as hexameric and higher-order complexes via N-terminal cysteine residues, when expressed in heterologous cells.\",\n      \"method\": \"Heterologous cell expression, biochemical fractionation, co-immunoprecipitation\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical characterization with multiple complex forms demonstrated, single lab, two orthogonal methods\",\n      \"pmids\": [\"20525073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CTRP13 forms heteromeric complexes with CTRP10 (C1QL2) when co-expressed; this heteromeric association does not involve conserved N-terminal Cys residues.\",\n      \"method\": \"Co-expression in heterologous cells, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mutagenesis distinguishing the interaction domain, single lab\",\n      \"pmids\": [\"21378161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CTRP11 forms heteromeric complexes with CTRP10 (C1QL2) via C-terminal globular domains when co-expressed.\",\n      \"method\": \"Co-expression in heterologous cells, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct co-IP with domain mapping, single lab\",\n      \"pmids\": [\"23449976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of the globular C1q-domain of C1QL2 reveal a trimeric arrangement with each protomer forming a jelly-roll fold of 10 β-strands; C1QL2 trimers contain four Ca2+-binding sites along the trimeric symmetry axis plus additional surface Ca2+-binding sites. Mutation of Ca2+-coordinating residues lowered Ca2+-binding affinity and protein stability.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, biophysical stability assays\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure combined with functional mutagenesis of Ca2+-binding residues\",\n      \"pmids\": [\"25752542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"C1QL1, C1QL2, and C1QL3 bind to brain-specific angiogenesis inhibitor 3 (BAI3), an adhesion-type GPCR implicated in dendritic morphology regulation via actin filament organization.\",\n      \"method\": \"Binding assay (structural study context, in vitro binding)\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding established in structural study context, single lab\",\n      \"pmids\": [\"25752542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"C1ql2 and C1ql3, produced by mossy fibers, serve as extracellular organizers that recruit functional postsynaptic kainate receptor (KAR) complexes at mossy fiber–CA3 synapses. C1ql2 specifically binds the amino-terminal domains of postsynaptic GluK2 and GluK4 KAR subunits and the presynaptic neurexin-3 containing exon 25b (splice site 5) in vitro. In C1ql2/3 double-null mice, CA3 synaptic responses lost the slow KAR-mediated components.\",\n      \"method\": \"In vitro binding assays (pulldown with recombinant proteins), genetic knockout mice, electrophysiology\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro binding with defined subunits, double-KO mouse electrophysiology confirming KAR loss-of-function, replicated across multiple orthogonal methods\",\n      \"pmids\": [\"27133466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"C1ql2 is a direct functional target of the transcription factor Bcl11b; Bcl11b regulates synaptic vesicle recruitment and long-term potentiation at mossy fiber–CA3 synapses through C1ql2. C1ql2 exerts its synaptic functions through direct interaction with neurexin-3 splice variant Nrxn3(25b+). Expression of a non-binding C1ql2 mutant or deletion of Nrxn3 in dentate gyrus granule neurons recapitulated the Bcl11b and C1ql2 mutant synaptic phenotypes.\",\n      \"method\": \"Genetic knockout/conditional deletion in mice, expression of non-binding mutant, in vivo and in vitro electrophysiology, molecular interaction assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — epistasis via genetic KO and rescue/dominant-negative, multiple orthogonal methods (KO, mutant expression, electrophysiology), rigorous controls\",\n      \"pmids\": [\"38358390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CTRP10 (C1QL2) negatively regulates body weight in female mice in a sexually dimorphic manner. Female, but not male, Ctrp10 knockout mice develop obesity on a low-fat diet while maintaining largely preserved insulin sensitivity, glucose tolerance, and metabolic health (no steatosis, dyslipidemia, or inflammation), uncoupling obesity from metabolic dysfunction.\",\n      \"method\": \"Constitutive knockout mice, metabolic phenotyping (glucose tolerance, insulin tolerance, body composition, plasma lipids), multi-tissue transcriptomics\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — constitutive KO with comprehensive metabolic phenotyping across multiple tissues and parameters, published in peer-reviewed journal\",\n      \"pmids\": [\"40126547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CTRP10 (C1QL2) is required for optimal motor function. Female Ctrp10 KO mice show impaired motor coordination (rotarod) and fine motor skills (beam walk, complex running wheel) with sex-biased effects. CTRP10 loss alters cerebellar and motor cortex pathways related to synaptic organization and mitochondrial respiration, and reduces mitochondrial respiration in the motor cortex.\",\n      \"method\": \"Constitutive knockout mice, behavioral testing (rotarod, beam walk, complex running wheel, grip strength), transcriptomic analysis, mitochondrial respiration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — constitutive KO with multiple orthogonal behavioral and molecular readouts, functional mitochondrial assay, single lab\",\n      \"pmids\": [\"41933728\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C1QL2/CTRP10 is a secreted C1q-family glycoprotein that forms trimers (and higher-order oligomers via N-terminal cysteine disulfide bonds) and functions as a transsynaptic organizer at hippocampal mossy fiber–CA3 synapses by binding presynaptic neurexin-3(25b+) and postsynaptic kainate receptor subunits GluK2/GluK4 to recruit functional KAR complexes, with its synaptic expression controlled by transcription factor Bcl11b; peripherally, CTRP10 negatively regulates female body weight, and its loss produces sex-biased motor coordination deficits accompanied by altered cerebellar/motor cortex gene expression and reduced mitochondrial respiration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C1QL2 (CTRP10) is a secreted C1q-family glycoprotein that acts as a transsynaptic organizer in the brain and as a sex-biased peripheral regulator of body weight and motor function [#6, #8]. The protein assembles into trimers as its basic structural unit, with each protomer adopting a jelly-roll globular C1q fold; trimers coordinate multiple Ca2+ ions along their symmetry axis and are further assembled into hexameric and higher-order oligomers through disulfide bonds formed by N-terminal cysteine residues [#0, #4]. Beyond homo-oligomerization, C1QL2 forms heteromeric complexes with related CTRP proteins through distinct interfaces—via C-terminal globular domains in the case of CTRP11 and through a cysteine-independent interface with CTRP13 [#2, #3]. At hippocampal mossy fiber–CA3 synapses, C1QL2 produced by mossy fibers bridges the synaptic cleft by binding presynaptic neurexin-3 containing exon 25b and the amino-terminal domains of postsynaptic kainate receptor subunits GluK2 and GluK4, thereby recruiting functional KAR complexes; loss of C1ql2/3 abolishes the slow KAR-mediated synaptic response [#6]. Its synaptic expression is a direct functional target of the transcription factor Bcl11b, and C1QL2 mediates Bcl11b-dependent synaptic vesicle recruitment and long-term potentiation through its interaction with Nrxn3(25b+) [#7]. C1QL2 also binds the adhesion-type GPCR BAI3 [#5]. Peripherally, C1QL2 negatively regulates female body weight, with Ctrp10 knockout females developing obesity uncoupled from metabolic dysfunction, and is required for optimal motor coordination, with its loss altering cerebellar and motor cortex synaptic and mitochondrial pathways and reducing motor cortex mitochondrial respiration [#8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the basic structural architecture of the secreted protein, showing it builds from trimers into higher-order oligomers via N-terminal cysteine disulfide bonds.\",\n      \"evidence\": \"Heterologous mammalian cell expression with SDS-PAGE, size exclusion, and cysteine mutagenesis\",\n      \"pmids\": [\"18783346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of oligomerization not addressed\", \"No physiological binding partners identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Confirmed secretion and extended the oligomerization model to include homomeric, heteromeric, and hexameric assemblies governed by N-terminal cysteines.\",\n      \"evidence\": \"Heterologous cell expression, biochemical fractionation, and co-immunoprecipitation\",\n      \"pmids\": [\"20525073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heteromeric partners not yet defined in this work\", \"In vivo relevance of complexes untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified CTRP13 as a heteromeric partner and showed this association uses an interface distinct from the conserved N-terminal cysteines, indicating multiple oligomerization modes.\",\n      \"evidence\": \"Co-expression in heterologous cells with co-immunoprecipitation and mutagenesis\",\n      \"pmids\": [\"21378161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological significance of the heteromer unknown\", \"Single-lab co-IP without reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped a second heteromeric partnership with CTRP11 to the C-terminal globular domains, defining domain-specific assembly rules for the family.\",\n      \"evidence\": \"Co-expression in heterologous cells with co-immunoprecipitation and domain mapping\",\n      \"pmids\": [\"23449976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional output of the CTRP11 heteromer not established\", \"No endogenous tissue confirmation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the atomic structure of the globular C1q domain and identified Ca2+-binding sites essential for protein stability, while also showing C1QL2 binds the adhesion-GPCR BAI3.\",\n      \"evidence\": \"X-ray crystallography, site-directed mutagenesis, biophysical stability assays, and in vitro binding\",\n      \"pmids\": [\"25752542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling consequence of BAI3 binding not defined\", \"Role of Ca2+ sites in receptor engagement untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined C1QL2's core synaptic function as a transsynaptic organizer bridging presynaptic neurexin-3(25b+) and postsynaptic GluK2/GluK4 to recruit functional kainate receptors at mossy fiber–CA3 synapses.\",\n      \"evidence\": \"In vitro pulldown with recombinant proteins, C1ql2/3 double-knockout mice, and electrophysiology\",\n      \"pmids\": [\"27133466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the transsynaptic complex unresolved\", \"Contribution of oligomeric state to bridging unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed C1QL2 downstream of the transcription factor Bcl11b and demonstrated that its Nrxn3(25b+) interaction is required for synaptic vesicle recruitment and long-term potentiation, establishing a transcription-to-synapse axis.\",\n      \"evidence\": \"Conditional knockout and Nrxn3 deletion in mice, non-binding mutant expression, in vivo/in vitro electrophysiology, and interaction assays\",\n      \"pmids\": [\"38358390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other Bcl11b targets contributing to phenotype not excluded\", \"Mechanism coupling KAR recruitment to LTP not fully detailed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a peripheral role: C1QL2 negatively regulates female body weight in a sexually dimorphic manner, uncoupling obesity from metabolic dysfunction.\",\n      \"evidence\": \"Constitutive knockout mice with comprehensive metabolic phenotyping and multi-tissue transcriptomics\",\n      \"pmids\": [\"40126547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue source and receptor mediating the metabolic effect unknown\", \"Mechanistic basis of sexual dimorphism unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended the loss-of-function phenotype to motor behavior, linking C1QL2 to cerebellar/motor cortex synaptic organization and mitochondrial respiration.\",\n      \"evidence\": \"Constitutive knockout mice, behavioral testing, transcriptomics, and mitochondrial respiration assays\",\n      \"pmids\": [\"41933728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between C1QL2 and mitochondrial respiration not established\", \"Whether motor deficit is cell-autonomous to specific neuron types unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How C1QL2's biochemical features—oligomeric state, Ca2+ coordination, and receptor binding—are integrated to produce both its central synaptic organizing function and its peripheral metabolic/motor roles remains unresolved.\",\n      \"evidence\": \"No single study connects the structural, synaptic, and peripheral findings mechanistically\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified receptor map across CNS and peripheral tissues\", \"Mechanism of sex-biased peripheral action undefined\", \"Functional relevance of CTRP heteromers in vivo untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NRXN3\", \"GRIK2\", \"GRIK4\", \"ADGRB3\", \"C1QL3\", \"CTRP11\", \"CTRP13\", \"BCL11B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}