{"gene":"C1QL2","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":2016,"finding":"C1ql2 and C1ql3, produced by mossy fibers, serve as extracellular organizers that recruit functional postsynaptic kainate receptor (KAR) complexes to CA3 pyramidal neurons by specifically binding the amino-terminal domains of postsynaptic GluK2 and GluK4 KAR subunits and the presynaptic neurexin-3 containing a specific splice-site 5 (exon 25b) sequence in vitro. In C1ql2/3 double-null mice, CA3 synaptic responses lost their slow, KAR-mediated components.","method":"In vitro binding assays, double-knockout mice, electrophysiology","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (in vitro binding, KO mice, electrophysiology), replicated across follow-up studies","pmids":["27133466"],"is_preprint":false},{"year":2015,"finding":"Crystal structures of the globular C1q-domains of C1QL1, C1QL2, and C1QL3 revealed that each forms a homotrimer with a jelly-roll fold of 10 β-strands; trimers may assemble into higher-order oligomers and 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, Ca2+-binding assays","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structures combined with mutagenesis and functional validation","pmids":["25752542"],"is_preprint":false},{"year":2015,"finding":"C1QL1, C1QL2, and C1QL3 bind to brain-specific angiogenesis inhibitor 3 (BAI3), an adhesion-type G-protein coupled receptor implicated in dendritic morphology via actin filament organization.","method":"Binding assays (structural study context), reported interaction with BAI3","journal":"Structure","confidence":"Medium","confidence_rationale":"Tier 3 — binding interaction reported in structural study; functional link to BAI3 signaling noted but not fully characterized in this paper","pmids":["25752542"],"is_preprint":false},{"year":2010,"finding":"C1QL2 (C1q-like subfamily) is a secreted protein that forms homomeric and heteromeric complexes; it assembles into hexameric and higher-order complexes via N-terminal cysteine residues. C1QL2 mRNA is strongly expressed in the dentate gyrus and appears at later embryonic stages compared to C1QL1 and C1QL3.","method":"Heterologous expression, biochemical characterization (secretion assay, oligomerization analysis), in situ hybridization","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical characterization in heterologous cells with multiple methods","pmids":["20525073"],"is_preprint":false},{"year":2008,"finding":"CTRP10/C1QL2 forms trimers as a basic structural unit and assembles into higher-order oligomeric complexes via disulfide bonding mediated by N-terminal cysteine residues. It also forms heteromeric complexes with CTRP13 (and other family members) when co-expressed in mammalian cells.","method":"Heterologous mammalian cell expression, biochemical oligomerization assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical characterization of oligomerization and heteromeric complex formation","pmids":["18783346"],"is_preprint":false},{"year":2024,"finding":"C1ql2 is a direct functional target of the transcription factor Bcl11b in dentate gyrus granule neurons. C1ql2 regulates synaptic vesicle recruitment and long-term potentiation at mossy fiber-CA3 synapses through direct interaction with a specific splice variant of neurexin-3, Nrxn3(25b+). A non-binding C1ql2 mutant or deletion of Nrxn3 in dentate gyrus granule neurons recapitulated the Bcl11b and C1ql2 mutant synaptic phenotypes.","method":"Conditional/constitutive knockout mice, ChIP/transcription factor target identification, electrophysiology (LTP assay), expression of non-binding mutant, in vivo and in vitro synaptic vesicle recruitment assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including KO mice, non-binding mutant rescue, electrophysiology, and transcription factor target validation","pmids":["38358390"],"is_preprint":false},{"year":2025,"finding":"CTRP10/C1QL2-deficient (knockout) female mice develop obesity with age while maintaining metabolic health (no steatosis, dyslipidemia, glucose intolerance, or insulin resistance), demonstrating that CTRP10 negatively regulates body weight in a sexually dimorphic manner. Multi-tissue transcriptomic analyses identified altered gene expression pathways associated with insulin-sensitive obesity.","method":"Constitutive knockout mice, metabolic phenotyping, multi-tissue transcriptomics","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined metabolic phenotype, but molecular mechanism of weight regulation not yet elucidated","pmids":["40126547"],"is_preprint":false},{"year":2026,"finding":"CTRP10/C1QL2-deficient (knockout) mice show impaired motor coordination and fine motor skills (rotarod, beam walk, complex running wheel), with female KO mice exhibiting more pronounced deficits. Loss of CTRP10 alters cerebellar and motor cortex pathways related to synaptic organization and reduces mitochondrial respiration in the motor cortex.","method":"Constitutive knockout mice, behavioral assays (rotarod, beam walk, running wheel, grip strength), transcriptomics, mitochondrial respiration assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with multiple behavioral and molecular readouts, but mechanistic pathway between C1QL2 and motor phenotype not fully defined","pmids":["41933728"],"is_preprint":false},{"year":2021,"finding":"Perinatal SSRI exposure increases mRNA expression of Bai3 and its C1ql ligands (including C1ql2) in the early postnatal dentate gyrus, and transient Bai3 knockdown in this context lessened behavioral consequences of SSRI exposure, placing C1ql2 in a BAI3 signaling pathway in the dentate gyrus.","method":"In vivo mRNA knockdown, qPCR expression analysis, behavioral assays","journal":"Neuroscience","confidence":"Low","confidence_rationale":"Tier 3 — pathway placement inferred from Bai3 KD and C1ql2 expression changes, no direct C1ql2 manipulation","pmids":["34293414"],"is_preprint":false},{"year":2025,"finding":"Virally expressed human mutant tau in anterodorsal nucleus of thalamus (ADn) of C1ql2-Cre mice caused reduced directionality and altered burst firing of head direction cells, and spatial disorientation behavior; this establishes C1ql2 expression as a marker of ADn neurons whose activity underlies head direction signaling.","method":"Viral tau expression in C1ql2-Cre mice, in vivo electrophysiology, behavioral assays","journal":"Cell reports","confidence":"Low","confidence_rationale":"Tier 3 — C1ql2-Cre used as a cell-type marker/tool; mechanistic role of C1ql2 itself not directly tested","pmids":["41275492"],"is_preprint":false}],"current_model":"C1QL2 (CTRP10) is a secreted, homotrimeric/hetero-oligomeric C1q-family protein expressed predominantly in neurons that functions as a transsynaptic organizer at hippocampal mossy fiber-CA3 synapses by binding the amino-terminal domains of kainate receptor subunits GluK2/GluK4 postsynaptically and neurexin-3 (splice variant Nrxn3(25b+)) presynaptically, thereby recruiting functional KAR complexes and regulating synaptic vesicle recruitment and LTP; this synaptic function is transcriptionally controlled by Bcl11b, and peripherally, CTRP10/C1QL2 negatively regulates body weight in a sexually dimorphic manner and is required for optimal motor coordination."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing the basic quaternary structure of C1QL2 answered how C1q-family members oligomerize: C1QL2 forms disulfide-bonded trimers that assemble into higher-order complexes and can hetero-oligomerize with other family members such as CTRP13.","evidence":"Heterologous mammalian cell expression with biochemical oligomerization assays","pmids":["18783346"],"confidence":"Medium","gaps":["Physiological relevance of heteromeric complexes not tested in vivo","Stoichiometry and architecture of higher-order oligomers unresolved"]},{"year":2010,"claim":"Demonstrating that C1QL2 is secreted and enriched in the dentate gyrus established its expression domain, pointing toward a function at hippocampal mossy fiber synapses.","evidence":"In situ hybridization, secretion assays, and oligomerization analysis in heterologous cells","pmids":["20525073"],"confidence":"Medium","gaps":["No receptor or binding partner identified at this stage","Functional consequence of dentate gyrus expression unknown"]},{"year":2015,"claim":"High-resolution crystal structures of the C1QL2 globular domain resolved the trimeric jelly-roll fold and identified Ca²⁺-binding sites critical for stability, providing the first atomic framework for understanding ligand interactions; in the same study, C1QL family members were shown to bind the adhesion GPCR BAI3.","evidence":"X-ray crystallography, site-directed mutagenesis of Ca²⁺-coordinating residues, Ca²⁺-binding assays, BAI3 binding assays","pmids":["25752542"],"confidence":"High","gaps":["Functional consequence of BAI3 binding by C1QL2 specifically not characterized","Whether Ca²⁺-binding sites regulate receptor interactions unknown"]},{"year":2016,"claim":"The central mechanistic question — what does C1QL2 organize at mossy fiber synapses — was answered by showing it bridges presynaptic neurexin-3 (exon 25b+ splice variant) and postsynaptic KAR subunits GluK2/GluK4, and that loss of C1ql2/3 eliminates slow KAR-mediated synaptic transmission at CA3.","evidence":"In vitro binding assays, C1ql2/C1ql3 double-knockout mice, electrophysiology at mossy fiber–CA3 synapses","pmids":["27133466"],"confidence":"High","gaps":["Individual contribution of C1QL2 versus C1QL3 not separated (double KO used)","Structural basis of C1QL2–GluK2/GluK4 and C1QL2–Nrxn3 interactions unresolved"]},{"year":2024,"claim":"The upstream transcriptional control and presynaptic mechanism were clarified: Bcl11b directly drives C1ql2 transcription in granule neurons, and C1QL2 interaction with Nrxn3(25b+) is required for synaptic vesicle recruitment and LTP, as shown by phenocopy between a non-binding C1ql2 mutant and Nrxn3 deletion.","evidence":"Conditional/constitutive KO mice, ChIP-based target identification, non-binding mutant rescue, electrophysiology (LTP), synaptic vesicle recruitment assays","pmids":["38358390"],"confidence":"High","gaps":["How C1QL2–Nrxn3 binding mechanistically triggers vesicle recruitment is unclear","Whether Bcl11b regulation is specific to dentate gyrus or extends to other C1QL2-expressing neurons unknown"]},{"year":2025,"claim":"Beyond the hippocampus, C1QL2 loss revealed a sexually dimorphic metabolic phenotype — female KO mice develop obesity while remaining insulin-sensitive — establishing a peripheral or central regulatory role in energy balance.","evidence":"Constitutive KO mice, metabolic phenotyping, multi-tissue transcriptomics","pmids":["40126547"],"confidence":"Medium","gaps":["Molecular mechanism of weight regulation (central vs. peripheral action) not defined","Receptor or signaling pathway mediating metabolic effects unknown","Basis of sexual dimorphism unresolved"]},{"year":2025,"claim":"Motor coordination deficits in C1QL2-KO mice linked the protein to cerebellar and motor cortex synaptic organization and mitochondrial function, broadening its physiological role beyond hippocampal KAR recruitment.","evidence":"Constitutive KO mice, rotarod/beam walk/running wheel behavioral assays, transcriptomics, mitochondrial respiration assay","pmids":["41933728"],"confidence":"Medium","gaps":["Direct synaptic mechanism in cerebellum/motor cortex not identified","Whether motor phenotype reflects Nrxn3/KAR-dependent or independent pathway unknown","Causal link between reduced mitochondrial respiration and motor deficits not established"]},{"year":null,"claim":"Open question: what receptor and signaling pathway mediates C1QL2's metabolic and motor functions outside the hippocampus, and how do BAI3 versus Nrxn3/KAR interactions partition across brain regions and peripheral tissues?","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of C1QL2 in complex with any receptor","Relative contributions of C1QL2 versus C1QL3 remain unresolved in single-KO models","Peripheral tissue expression and function largely uncharacterized at the molecular level"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,3,4]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,5]}],"complexes":[],"partners":["NRXN3","GRIK2","GRIK4","C1QL3","ADGRB3"],"other_free_text":[]},"mechanistic_narrative":"C1QL2 is a secreted, C1q-domain family glycoprotein that functions as a transsynaptic organizer at hippocampal mossy fiber–CA3 synapses and contributes to peripheral energy homeostasis. The protein assembles into homotrimers via a jelly-roll β-strand fold with Ca²⁺-binding sites and further oligomerizes through N-terminal cysteine-mediated disulfide bonds; it can also form heteromeric complexes with other C1q-family members [PMID:25752542, PMID:18783346]. At mossy fiber–CA3 synapses, C1QL2 bridges presynaptic neurexin-3 (Nrxn3 25b+ splice variant) and postsynaptic kainate receptor subunits GluK2/GluK4, thereby recruiting functional KAR complexes, regulating synaptic vesicle recruitment, and supporting long-term potentiation; this synaptic role is transcriptionally controlled by Bcl11b in dentate gyrus granule neurons [PMID:27133466, PMID:38358390]. Loss of C1QL2 in female mice produces age-dependent obesity without classical metabolic dysfunction and impairs motor coordination, indicating additional roles outside the hippocampus [PMID:40126547, PMID:41933728]."},"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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neurons by specifically binding the amino-terminal domains of postsynaptic GluK2 and GluK4 KAR subunits and the presynaptic neurexin-3 containing a specific splice-site 5 (exon 25b) sequence in vitro. In C1ql2/3 double-null mice, CA3 synaptic responses lost their slow, KAR-mediated components.\",\n      \"method\": \"In vitro binding assays, double-knockout mice, electrophysiology\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (in vitro binding, KO mice, electrophysiology), replicated across follow-up studies\",\n      \"pmids\": [\"27133466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of the globular C1q-domains of C1QL1, C1QL2, and C1QL3 revealed that each forms a homotrimer with a jelly-roll fold of 10 β-strands; trimers may assemble into higher-order oligomers and 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, Ca2+-binding assays\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structures combined with mutagenesis and functional validation\",\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 G-protein coupled receptor implicated in dendritic morphology via actin filament organization.\",\n      \"method\": \"Binding assays (structural study context), reported interaction with BAI3\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — binding interaction reported in structural study; functional link to BAI3 signaling noted but not fully characterized in this paper\",\n      \"pmids\": [\"25752542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C1QL2 (C1q-like subfamily) is a secreted protein that forms homomeric and heteromeric complexes; it assembles into hexameric and higher-order complexes via N-terminal cysteine residues. C1QL2 mRNA is strongly expressed in the dentate gyrus and appears at later embryonic stages compared to C1QL1 and C1QL3.\",\n      \"method\": \"Heterologous expression, biochemical characterization (secretion assay, oligomerization analysis), in situ hybridization\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical characterization in heterologous cells with multiple methods\",\n      \"pmids\": [\"20525073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CTRP10/C1QL2 forms trimers as a basic structural unit and assembles into higher-order oligomeric complexes via disulfide bonding mediated by N-terminal cysteine residues. It also forms heteromeric complexes with CTRP13 (and other family members) when co-expressed in mammalian cells.\",\n      \"method\": \"Heterologous mammalian cell expression, biochemical oligomerization assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical characterization of oligomerization and heteromeric complex formation\",\n      \"pmids\": [\"18783346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"C1ql2 is a direct functional target of the transcription factor Bcl11b in dentate gyrus granule neurons. C1ql2 regulates synaptic vesicle recruitment and long-term potentiation at mossy fiber-CA3 synapses through direct interaction with a specific splice variant of neurexin-3, Nrxn3(25b+). A non-binding C1ql2 mutant or deletion of Nrxn3 in dentate gyrus granule neurons recapitulated the Bcl11b and C1ql2 mutant synaptic phenotypes.\",\n      \"method\": \"Conditional/constitutive knockout mice, ChIP/transcription factor target identification, electrophysiology (LTP assay), expression of non-binding mutant, in vivo and in vitro synaptic vesicle recruitment assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including KO mice, non-binding mutant rescue, electrophysiology, and transcription factor target validation\",\n      \"pmids\": [\"38358390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CTRP10/C1QL2-deficient (knockout) female mice develop obesity with age while maintaining metabolic health (no steatosis, dyslipidemia, glucose intolerance, or insulin resistance), demonstrating that CTRP10 negatively regulates body weight in a sexually dimorphic manner. Multi-tissue transcriptomic analyses identified altered gene expression pathways associated with insulin-sensitive obesity.\",\n      \"method\": \"Constitutive knockout mice, metabolic phenotyping, multi-tissue transcriptomics\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined metabolic phenotype, but molecular mechanism of weight regulation not yet elucidated\",\n      \"pmids\": [\"40126547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CTRP10/C1QL2-deficient (knockout) mice show impaired motor coordination and fine motor skills (rotarod, beam walk, complex running wheel), with female KO mice exhibiting more pronounced deficits. Loss of CTRP10 alters cerebellar and motor cortex pathways related to synaptic organization and reduces mitochondrial respiration in the motor cortex.\",\n      \"method\": \"Constitutive knockout mice, behavioral assays (rotarod, beam walk, running wheel, grip strength), transcriptomics, mitochondrial respiration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple behavioral and molecular readouts, but mechanistic pathway between C1QL2 and motor phenotype not fully defined\",\n      \"pmids\": [\"41933728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Perinatal SSRI exposure increases mRNA expression of Bai3 and its C1ql ligands (including C1ql2) in the early postnatal dentate gyrus, and transient Bai3 knockdown in this context lessened behavioral consequences of SSRI exposure, placing C1ql2 in a BAI3 signaling pathway in the dentate gyrus.\",\n      \"method\": \"In vivo mRNA knockdown, qPCR expression analysis, behavioral assays\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pathway placement inferred from Bai3 KD and C1ql2 expression changes, no direct C1ql2 manipulation\",\n      \"pmids\": [\"34293414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Virally expressed human mutant tau in anterodorsal nucleus of thalamus (ADn) of C1ql2-Cre mice caused reduced directionality and altered burst firing of head direction cells, and spatial disorientation behavior; this establishes C1ql2 expression as a marker of ADn neurons whose activity underlies head direction signaling.\",\n      \"method\": \"Viral tau expression in C1ql2-Cre mice, in vivo electrophysiology, behavioral assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — C1ql2-Cre used as a cell-type marker/tool; mechanistic role of C1ql2 itself not directly tested\",\n      \"pmids\": [\"41275492\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C1QL2 (CTRP10) is a secreted, homotrimeric/hetero-oligomeric C1q-family protein expressed predominantly in neurons that functions as a transsynaptic organizer at hippocampal mossy fiber-CA3 synapses by binding the amino-terminal domains of kainate receptor subunits GluK2/GluK4 postsynaptically and neurexin-3 (splice variant Nrxn3(25b+)) presynaptically, thereby recruiting functional KAR complexes and regulating synaptic vesicle recruitment and LTP; this synaptic function is transcriptionally controlled by Bcl11b, and peripherally, CTRP10/C1QL2 negatively regulates body weight in a sexually dimorphic manner and is required for optimal motor coordination.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"C1QL2 is a secreted, C1q-domain family glycoprotein that functions as a transsynaptic organizer at hippocampal mossy fiber–CA3 synapses and contributes to peripheral energy homeostasis. The protein assembles into homotrimers via a jelly-roll β-strand fold with Ca²⁺-binding sites and further oligomerizes through N-terminal cysteine-mediated disulfide bonds; it can also form heteromeric complexes with other C1q-family members [PMID:25752542, PMID:18783346]. At mossy fiber–CA3 synapses, C1QL2 bridges presynaptic neurexin-3 (Nrxn3 25b+ splice variant) and postsynaptic kainate receptor subunits GluK2/GluK4, thereby recruiting functional KAR complexes, regulating synaptic vesicle recruitment, and supporting long-term potentiation; this synaptic role is transcriptionally controlled by Bcl11b in dentate gyrus granule neurons [PMID:27133466, PMID:38358390]. Loss of C1QL2 in female mice produces age-dependent obesity without classical metabolic dysfunction and impairs motor coordination, indicating additional roles outside the hippocampus [PMID:40126547, PMID:41933728].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing the basic quaternary structure of C1QL2 answered how C1q-family members oligomerize: C1QL2 forms disulfide-bonded trimers that assemble into higher-order complexes and can hetero-oligomerize with other family members such as CTRP13.\",\n      \"evidence\": \"Heterologous mammalian cell expression with biochemical oligomerization assays\",\n      \"pmids\": [\"18783346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Physiological relevance of heteromeric complexes not tested in vivo\",\n        \"Stoichiometry and architecture of higher-order oligomers unresolved\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that C1QL2 is secreted and enriched in the dentate gyrus established its expression domain, pointing toward a function at hippocampal mossy fiber synapses.\",\n      \"evidence\": \"In situ hybridization, secretion assays, and oligomerization analysis in heterologous cells\",\n      \"pmids\": [\"20525073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No receptor or binding partner identified at this stage\",\n        \"Functional consequence of dentate gyrus expression unknown\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"High-resolution crystal structures of the C1QL2 globular domain resolved the trimeric jelly-roll fold and identified Ca²⁺-binding sites critical for stability, providing the first atomic framework for understanding ligand interactions; in the same study, C1QL family members were shown to bind the adhesion GPCR BAI3.\",\n      \"evidence\": \"X-ray crystallography, site-directed mutagenesis of Ca²⁺-coordinating residues, Ca²⁺-binding assays, BAI3 binding assays\",\n      \"pmids\": [\"25752542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of BAI3 binding by C1QL2 specifically not characterized\",\n        \"Whether Ca²⁺-binding sites regulate receptor interactions unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The central mechanistic question — what does C1QL2 organize at mossy fiber synapses — was answered by showing it bridges presynaptic neurexin-3 (exon 25b+ splice variant) and postsynaptic KAR subunits GluK2/GluK4, and that loss of C1ql2/3 eliminates slow KAR-mediated synaptic transmission at CA3.\",\n      \"evidence\": \"In vitro binding assays, C1ql2/C1ql3 double-knockout mice, electrophysiology at mossy fiber–CA3 synapses\",\n      \"pmids\": [\"27133466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Individual contribution of C1QL2 versus C1QL3 not separated (double KO used)\",\n        \"Structural basis of C1QL2–GluK2/GluK4 and C1QL2–Nrxn3 interactions unresolved\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The upstream transcriptional control and presynaptic mechanism were clarified: Bcl11b directly drives C1ql2 transcription in granule neurons, and C1QL2 interaction with Nrxn3(25b+) is required for synaptic vesicle recruitment and LTP, as shown by phenocopy between a non-binding C1ql2 mutant and Nrxn3 deletion.\",\n      \"evidence\": \"Conditional/constitutive KO mice, ChIP-based target identification, non-binding mutant rescue, electrophysiology (LTP), synaptic vesicle recruitment assays\",\n      \"pmids\": [\"38358390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How C1QL2–Nrxn3 binding mechanistically triggers vesicle recruitment is unclear\",\n        \"Whether Bcl11b regulation is specific to dentate gyrus or extends to other C1QL2-expressing neurons unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Beyond the hippocampus, C1QL2 loss revealed a sexually dimorphic metabolic phenotype — female KO mice develop obesity while remaining insulin-sensitive — establishing a peripheral or central regulatory role in energy balance.\",\n      \"evidence\": \"Constitutive KO mice, metabolic phenotyping, multi-tissue transcriptomics\",\n      \"pmids\": [\"40126547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism of weight regulation (central vs. peripheral action) not defined\",\n        \"Receptor or signaling pathway mediating metabolic effects unknown\",\n        \"Basis of sexual dimorphism unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Motor coordination deficits in C1QL2-KO mice linked the protein to cerebellar and motor cortex synaptic organization and mitochondrial function, broadening its physiological role beyond hippocampal KAR recruitment.\",\n      \"evidence\": \"Constitutive KO mice, rotarod/beam walk/running wheel behavioral assays, transcriptomics, mitochondrial respiration assay\",\n      \"pmids\": [\"41933728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct synaptic mechanism in cerebellum/motor cortex not identified\",\n        \"Whether motor phenotype reflects Nrxn3/KAR-dependent or independent pathway unknown\",\n        \"Causal link between reduced mitochondrial respiration and motor deficits not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Open question: what receptor and signaling pathway mediates C1QL2's metabolic and motor functions outside the hippocampus, and how do BAI3 versus Nrxn3/KAR interactions partition across brain regions and peripheral tissues?\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structure of C1QL2 in complex with any receptor\",\n        \"Relative contributions of C1QL2 versus C1QL3 remain unresolved in single-KO models\",\n        \"Peripheral tissue expression and function largely uncharacterized at the molecular level\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NRXN3\",\n      \"GRIK2\",\n      \"GRIK4\",\n      \"C1QL3\",\n      \"ADGRB3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}