{"gene":"SRGAP2C","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2012,"finding":"SRGAP2C encodes a truncated F-BAR domain protein that dimerizes with ancestral SRGAP2A (SRGAP2) to inhibit its function. Expression of SRGAP2C in mouse neocortex phenocopies SRGAP2 deficiency, leading to sustained radial migration, neoteny during spine maturation, and increased density of longer spines.","method":"Transgenic mouse expression, Co-immunoprecipitation (dimerization), loss-of-function comparison, neuronal morphology assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing dimerization, transgenic mouse phenotype with multiple orthogonal readouts, replicated across labs","pmids":["22559944"],"is_preprint":false},{"year":2012,"finding":"SRGAP2C arose ~2.4 mya as a partial duplication encoding only the promoter and first nine exons of SRGAP2A, resulting in a truncated protein. Sequence and expression analyses indicate SRGAP2C is the most fixed human-specific duplicate and most likely to encode a functional protein that antagonizes parental SRGAP2A function immediately at birth.","method":"Genomic sequencing of haploid hydatidiform mole, comparative sequence analysis, expression analysis","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genomic and expression analysis in single study; functional antagonism inferred from sequence but supported by companion paper","pmids":["22559943"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of SRGAP2A revealed it homodimerizes through a large interface including an F-BAR domain, a newly identified F-BAR extension (Fx), and RhoGAP-SH3 domains, with an unusual inverse geometry enabling associations with lamellipodia and dendritic spine heads. SRGAP2C carries a defective Fx-domain that severely compromises its solubility and membrane-scaffolding ability; SRGAP2A:SRGAP2C heterodimers form but are insoluble, thereby inhibiting SRGAP2A activity. The modern form of SRGAP2C (from ~2.4 mya) is more effective at heterodimerizing with SRGAP2A than the primal form.","method":"X-ray crystallography of SRGAP2A, in vitro heterodimerization assays, solubility assays, cell culture membrane-scaffolding assays, mutagenesis","journal":"Molecular biology and evolution","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determination plus in vitro reconstitution of dimerization and solubility assays, single lab but multiple orthogonal methods","pmids":["28333212"],"is_preprint":false},{"year":2019,"finding":"SRGAP2C and SRGAP2B are intrinsically unstable proteins in neurons; upon heterodimerization with SRGAP2A, they reduce SRGAP2A levels in a proteasome-dependent manner. SRGAP2C uniquely (compared to SRGAP2B) induces long-lasting changes in synaptic density throughout adulthood, due to specific non-synonymous mutations targeting arginine residues that enhance its ability to inhibit SRGAP2A and increase both excitatory and inhibitory synapse density with protracted maturation.","method":"Neuronal expression of SRGAP2B and SRGAP2C, proteasome inhibitor assays, heterodimerization assays, site-directed mutagenesis of arginine residues, synaptic density quantification across developmental stages","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteasome inhibition, mutagenesis, Co-IP, longitudinal synaptic assays) in single lab","pmids":["31822692"],"is_preprint":false},{"year":2021,"finding":"SRGAP2C expression in mice specifically increases local and long-range cortico-cortical connections onto layer 2/3 pyramidal neurons, shifts the fraction of layer 2/3 PNs activated by sensory stimulation, and enhances cortex-dependent sensory-discrimination learning. Computational modelling showed that increased layer 4 to layer 2/3 connectivity induced by SRGAP2C explains key changes in sensory coding.","method":"Transgenic mouse expression (all cortical PNs), viral circuit tracing, in vivo calcium imaging, sensory discrimination behavioral task, computational modelling","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal circuit and behavioral methods, replicated across multiple measures in single rigorous study","pmids":["34707291"],"is_preprint":false},{"year":2024,"finding":"SRGAP2C enhances synaptic accumulation of CTNND2 (delta-catenin) in human neurons. CTNND2 was identified as a major binding partner of SRGAP2A/SRGAP2C and acts downstream to slow synaptic maturation; CTNND2 deficiency leads to synaptic loss of SYNGAP1. This pathway links human-specific SRGAP2C activity to synaptic neoteny via CTNND2 regulation.","method":"Co-immunoprecipitation (SRGAP2-CTNND2 interaction), loss-of-function of CTNND2 in neurons, quantification of synaptic CTNND2 accumulation in human neurons expressing SRGAP2C, synaptic maturation assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and neuronal loss-of-function with synaptic readouts, single lab","pmids":["39352808"],"is_preprint":false},{"year":2024,"finding":"In transgenic cynomolgus macaques carrying SRGAP2C, delayed brain development was observed with increased deep-layer neurons during fetal neurogenesis and delayed synaptic maturation in adolescence, alongside neotenic transcriptome expression in pathways related to neuron ensheathment, synaptic connections, extracellular matrix, and energy metabolism.","method":"Transgenic macaque generation, longitudinal MRI imaging, histological quantification of cortical neurons, transcriptome analysis, behavioral cognitive testing","journal":"National science review","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic primate model with multiple cellular and imaging readouts, single lab","pmids":["38090550"],"is_preprint":false},{"year":2024,"finding":"In zebrafish, srgap2 knockout larvae phenocopy 'humanized' SRGAP2C-expressing larvae, including altered morphometric features, differential expression of synapse-, axonogenesis-, and vision-related genes, skewed excitatory/inhibitory neuron balance, seizure susceptibility, altered microglial membrane dynamics and delayed microglial maturation, and increased sensitivity to visual cues. Comparison of human (+SRGAP2C) vs. non-human primate (-SRGAP2C) transcriptomes in microglia showed overlapping gene alterations with zebrafish srgap2 mutants.","method":"Zebrafish srgap2 knockout, SRGAP2C transgenic zebrafish, single-cell RNA sequencing, behavioral seizure assays, live microglial imaging, visual sensitivity assays, cross-species transcriptome comparison","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (scRNA-seq, live imaging, behavioral assays) in zebrafish model, preprint not yet peer-reviewed","pmids":["39314374"],"is_preprint":true},{"year":2025,"finding":"A massively parallel reporter assay identified differentially active cis-regulatory elements (CREs) within the SRGAP2C locus that may contribute to paralog-specific expression patterns. Validated CREs for SRGAP2C showed differential activity compared to the ancestral chimpanzee ortholog, suggesting regulatory divergence contributes moderately to SRGAP2C-specific expression.","method":"Massively parallel reporter assay (MPRA) in lymphoblastoid and neuroblastoma cell lines, long-read expression and epigenomic data, CRE validation","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — reporter assay establishes CRE activity but functional consequence for SRGAP2C protein is inferred; preprint, single lab","pmids":["41292788"],"is_preprint":true}],"current_model":"SRGAP2C is a human-specific truncated paralog of SRGAP2A that encodes a defective F-BAR/Fx domain protein; it heterodimerizes with full-length SRGAP2A, forming insoluble complexes that inhibit SRGAP2A function and reduce its levels via proteasome-dependent degradation, thereby increasing excitatory and inhibitory synapse density, prolonging synapse maturation (neoteny), enhancing cortico-cortical connectivity, and promoting accumulation of the synaptic regulator CTNND2 — collectively contributing to human-specific features of neocortical development and circuit function."},"narrative":{"mechanistic_narrative":"SRGAP2C is a human-specific, partially duplicated paralog of SRGAP2A that arose ~2.4 mya and encodes a truncated F-BAR domain protein which acts as a dominant antagonist of its ancestral parent, contributing to human-specific features of neocortical development [PMID:22559944, PMID:22559943]. The duplication retained only the promoter and first nine exons of SRGAP2A, producing a protein with a defective F-BAR extension (Fx) domain that is poorly soluble and unable to scaffold membranes; SRGAP2C nonetheless heterodimerizes with full-length SRGAP2A through the F-BAR/Fx and RhoGAP-SH3 interface, and the resulting heterodimers are insoluble and functionally inhibitory [PMID:28333212]. In neurons SRGAP2C is intrinsically unstable, and upon heterodimerization it reduces SRGAP2A levels in a proteasome-dependent manner; human-specific arginine substitutions enhance this inhibitory capacity and drive long-lasting increases in both excitatory and inhibitory synapse density with protracted (neotenic) maturation [PMID:31822692]. Functionally, expression of SRGAP2C in mouse cortex phenocopies SRGAP2 deficiency — sustained radial migration, neotenic spine maturation, and increased density of longer spines [PMID:22559944] — and specifically increases local and long-range cortico-cortical connectivity onto layer 2/3 pyramidal neurons, reshaping sensory coding and enhancing sensory-discrimination learning [PMID:34707291]. Downstream, SRGAP2C enhances synaptic accumulation of its binding partner CTNND2 (delta-catenin), which slows synaptic maturation and supports synaptic SYNGAP1 retention, linking SRGAP2C activity to synaptic neoteny [PMID:39352808]. Transgenic primate and zebrafish models reproduce delayed neurodevelopment and neotenic transcriptomic and circuit phenotypes [PMID:38090550, PMID:39314374].","teleology":[{"year":2012,"claim":"Established that SRGAP2C is not a pseudogene but a functional human-specific paralog that antagonizes ancestral SRGAP2A, answering whether the duplication had a biological consequence for cortical development.","evidence":"Transgenic mouse neocortical expression, reciprocal Co-IP for dimerization, and neuronal morphology assays compared against SRGAP2 loss-of-function","pmids":["22559944","22559943"],"confidence":"High","gaps":["The structural basis for how a truncated protein inhibits the full-length parent was not resolved","Whether inhibition occurs by sequestration, degradation, or steric block was undefined","Synaptic and circuit-level consequences in adult cortex were not addressed"]},{"year":2017,"claim":"Defined the molecular mechanism of antagonism by showing SRGAP2A homodimerizes through an F-BAR/Fx/RhoGAP-SH3 interface and that SRGAP2C's defective Fx domain produces insoluble, non-functional heterodimers.","evidence":"X-ray crystallography of SRGAP2A plus in vitro heterodimerization, solubility, membrane-scaffolding, and mutagenesis assays","pmids":["28333212"],"confidence":"High","gaps":["Did not establish how insoluble heterodimers are handled in neurons (e.g. degradation)","No structure of the SRGAP2A:SRGAP2C heterodimer itself","Link between solubility defect and synaptic phenotype remained indirect"]},{"year":2019,"claim":"Connected heterodimerization to a degradative outcome and identified the specific arginine substitutions that make SRGAP2C a more potent and durable inhibitor than the paralog SRGAP2B.","evidence":"Neuronal expression of SRGAP2B/2C, proteasome inhibitor assays, site-directed mutagenesis of arginine residues, and longitudinal synaptic density quantification","pmids":["31822692"],"confidence":"High","gaps":["The E3 ligase and recognition pathway targeting SRGAP2A for degradation were not identified","How proteasomal turnover translates to sustained adult synaptic changes was not mechanistically traced"]},{"year":2021,"claim":"Demonstrated that SRGAP2C reshapes cortical circuit architecture and behavior, moving beyond single-cell morphology to network-level function.","evidence":"Transgenic mouse expression in cortical pyramidal neurons with viral tracing, in vivo calcium imaging, sensory-discrimination behavior, and computational modelling","pmids":["34707291"],"confidence":"High","gaps":["The molecular intermediary linking SRGAP2A inhibition to specific connectivity changes was not identified","Results obtained in mouse cortex; primate-specific effects untested here"]},{"year":2024,"claim":"Identified CTNND2 as a downstream synaptic effector, defining a molecular pathway from SRGAP2C to synaptic neoteny.","evidence":"Co-IP mapping the SRGAP2-CTNND2 interaction, CTNND2 loss-of-function in neurons, and quantification of synaptic CTNND2 accumulation in human neurons expressing SRGAP2C","pmids":["39352808"],"confidence":"Medium","gaps":["Whether CTNND2 accumulation is necessary for all SRGAP2C circuit phenotypes was not established","The mechanism by which reduced SRGAP2A increases synaptic CTNND2 was not fully resolved","Single lab, reciprocal Co-IP without orthogonal interaction validation"]},{"year":2024,"claim":"Extended SRGAP2C's developmental effects to a primate model, testing whether the gene drives neotenic phenotypes in a brain closer to human.","evidence":"Transgenic cynomolgus macaque generation with longitudinal MRI, histological neuron quantification, transcriptomics, and cognitive testing","pmids":["38090550"],"confidence":"Medium","gaps":["Causal link between transcriptomic neoteny and behavioral outcomes not established","Small cohort inherent to transgenic primate studies","Cell-type-specific mechanism in macaque cortex not dissected"]},{"year":2024,"claim":"Showed via zebrafish that loss of srgap2 and gain of SRGAP2C converge on shared phenotypes, including microglial and excitatory/inhibitory balance changes, broadening the cellular scope beyond pyramidal neurons.","evidence":"Zebrafish srgap2 knockout and SRGAP2C transgenics with scRNA-seq, live microglial imaging, behavioral seizure and visual assays, and cross-species transcriptome comparison (preprint)","pmids":["39314374"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Microglial effects of SRGAP2C in mammalian systems not confirmed","Whether zebrafish phenotypes reflect the same molecular antagonism mechanism is inferred"]},{"year":2025,"claim":"Began addressing how SRGAP2C achieves paralog-specific expression by identifying differentially active cis-regulatory elements within the locus.","evidence":"Massively parallel reporter assay in lymphoblastoid and neuroblastoma lines with long-read expression/epigenomic data and CRE validation (preprint)","pmids":["41292788"],"confidence":"Low","gaps":["Reporter activity establishes CRE function but consequence for endogenous SRGAP2C protein is inferred; preprint, single lab","No demonstration that the CREs control native SRGAP2C levels in neurons","Regulatory contribution quantified only as moderate"]},{"year":null,"claim":"The E3 ligase and degradation machinery that clear SRGAP2A:SRGAP2C heterodimers, and whether CTNND2 accumulation is required for SRGAP2C's circuit-level and behavioral effects, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified ubiquitin ligase for proteasome-dependent SRGAP2A reduction","Necessity of CTNND2 for connectivity and behavioral phenotypes untested","Structure of the inhibitory heterodimer not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,6]}],"complexes":["SRGAP2A:SRGAP2C heterodimer"],"partners":["SRGAP2A","CTNND2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P0DJJ0","full_name":"SLIT-ROBO Rho GTPase-activating protein 2C","aliases":["SLIT-ROBO Rho GTPase activating protein 2 pseudogene 1"],"length_aa":459,"mass_kda":53.5,"function":"Human-specific protein that acts as a key modifier of cortical connectivity in the human brain (PubMed:22559944, PubMed:27373832, PubMed:34707291). Acts by inhibiting the functions of ancestral paralog SRGAP2/SRGAP2A, a postsynaptic protein that regulates excitatory and inhibitory synapse maturation and density in cortical pyramidal neurons (PubMed:22559944, PubMed:27373832). SRGAP2C is unstable but is able to heterodimerize with SRGAP2/SRGAP2A, thereby reducing SRGAP2/SRGAP2A levels through proteasome-dependent degradation (PubMed:27373832, PubMed:28333212, PubMed:31822692). Inhibition of SRGAP2/SRGAP2A by SRGAP2C leads to an increase in synaptic density and protracted synaptic maturation of both excitatory and inhibitory synapses (PubMed:27373832, PubMed:34707291). Modifies cortical circuit connectivity by increasing the number of local and long-range cortical inputs received by layer 2/3 pyramidal neurons (PubMed:34707291). Also able to increase the probability of sensory-evoked responses by layer 2/3 pyramidal neurons (PubMed:34707291)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P0DJJ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SRGAP2C","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":5,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SRGAP2C","total_profiled":1310},"omim":[{"mim_id":"614705","title":"SLIT-ROBO RHO GTPase-ACTIVATING PROTEIN 2D; SRGAP2D","url":"https://www.omim.org/entry/614705"},{"mim_id":"614704","title":"SLIT-ROBO RHO GTPase-ACTIVATING PROTEIN 2C; SRGAP2C","url":"https://www.omim.org/entry/614704"},{"mim_id":"614703","title":"SLIT-ROBO RHO GTPase-ACTIVATING PROTEIN 2B; SRGAP2B","url":"https://www.omim.org/entry/614703"},{"mim_id":"606524","title":"SLIT-ROBO RHO GTPase-ACTIVATING PROTEIN 2; SRGAP2","url":"https://www.omim.org/entry/606524"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":33.8}],"url":"https://www.proteinatlas.org/search/SRGAP2C"},"hgnc":{"alias_symbol":[],"prev_symbol":["SRGAP2P1"]},"alphafold":{"accession":"P0DJJ0","domains":[{"cath_id":"1.20.1270.60","chopping":"11-81_91-197_221-312","consensus_level":"high","plddt":93.1816,"start":11,"end":312},{"cath_id":"-","chopping":"361-406_428-459","consensus_level":"medium","plddt":90.0801,"start":361,"end":459}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P0DJJ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-P0DJJ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P0DJJ0-F1-predicted_aligned_error_v6.png","plddt_mean":87.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRGAP2C","jax_strain_url":"https://www.jax.org/strain/search?query=SRGAP2C"},"sequence":{"accession":"P0DJJ0","fasta_url":"https://rest.uniprot.org/uniprotkb/P0DJJ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P0DJJ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P0DJJ0"}},"corpus_meta":[{"pmid":"22559944","id":"PMC_22559944","title":"Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22559944","citation_count":328,"is_preprint":false},{"pmid":"22559943","id":"PMC_22559943","title":"Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22559943","citation_count":296,"is_preprint":false},{"pmid":"27584858","id":"PMC_27584858","title":"Human adaptation and evolution by segmental duplication.","date":"2016","source":"Current opinion in genetics & development","url":"https://pubmed.ncbi.nlm.nih.gov/27584858","citation_count":138,"is_preprint":false},{"pmid":"28580430","id":"PMC_28580430","title":"The evolution and population diversity of human-specific segmental duplications.","date":"2017","source":"Nature ecology & evolution","url":"https://pubmed.ncbi.nlm.nih.gov/28580430","citation_count":117,"is_preprint":false},{"pmid":"34707291","id":"PMC_34707291","title":"A human-specific modifier of cortical connectivity and circuit function.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34707291","citation_count":63,"is_preprint":false},{"pmid":"31822692","id":"PMC_31822692","title":"The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31822692","citation_count":50,"is_preprint":false},{"pmid":"28333212","id":"PMC_28333212","title":"Structural History of Human SRGAP2 Proteins.","date":"2017","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/28333212","citation_count":32,"is_preprint":false},{"pmid":"39352808","id":"PMC_39352808","title":"CTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39352808","citation_count":20,"is_preprint":false},{"pmid":"36703164","id":"PMC_36703164","title":"Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry.","date":"2023","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36703164","citation_count":13,"is_preprint":false},{"pmid":"38090550","id":"PMC_38090550","title":"Brain developmental and cortical connectivity changes in transgenic monkeys carrying the human-specific duplicated gene SRGAP2C.","date":"2023","source":"National science review","url":"https://pubmed.ncbi.nlm.nih.gov/38090550","citation_count":8,"is_preprint":false},{"pmid":"35629083","id":"PMC_35629083","title":"Obesity-Associated Differentially Methylated Regions in Colon Cancer.","date":"2022","source":"Journal of personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35629083","citation_count":7,"is_preprint":false},{"pmid":"35571069","id":"PMC_35571069","title":"Differential Long Non-Coding RNA Expression Analysis in Chronic Non-Atrophic Gastritis, Gastric Mucosal Intraepithelial Neoplasia, and Gastric Cancer Tissues.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35571069","citation_count":7,"is_preprint":false},{"pmid":"39228737","id":"PMC_39228737","title":"The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations.","date":"2024","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39228737","citation_count":3,"is_preprint":false},{"pmid":"40565594","id":"PMC_40565594","title":"Origin and Evolution of Genes in Eukaryotes: Mechanisms, Dynamics, and Functional Implications.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/40565594","citation_count":3,"is_preprint":false},{"pmid":"39314374","id":"PMC_39314374","title":"Zebrafish models of human-duplicated SRGAP2 reveal novel functions in microglia and visual system development.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39314374","citation_count":3,"is_preprint":false},{"pmid":"39510039","id":"PMC_39510039","title":"Rev or restrain: Mechanisms of human-specific synaptic neoteny.","date":"2024","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/39510039","citation_count":0,"is_preprint":false},{"pmid":"41292788","id":"PMC_41292788","title":"Influence of cis-regulatory elements on expression divergence in human segmental duplications.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41292788","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.03.680410","title":"Influence of  <i>cis</i>  -regulatory elements on expression divergence in human segmental duplications","date":"2025-10-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.03.680410","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.11.612570","title":"Zebrafish models of human-duplicated  <i>SRGAP2</i>  reveal novel functions in microglia and visual system development","date":"2024-09-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.11.612570","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11547,"output_tokens":2572,"usd":0.03661,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9795,"output_tokens":3476,"usd":0.067937,"stage2_stop_reason":"end_turn"},"total_usd":0.104547,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"SRGAP2C encodes a truncated F-BAR domain protein that dimerizes with ancestral SRGAP2A (SRGAP2) to inhibit its function. Expression of SRGAP2C in mouse neocortex phenocopies SRGAP2 deficiency, leading to sustained radial migration, neoteny during spine maturation, and increased density of longer spines.\",\n      \"method\": \"Transgenic mouse expression, Co-immunoprecipitation (dimerization), loss-of-function comparison, neuronal morphology assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing dimerization, transgenic mouse phenotype with multiple orthogonal readouts, replicated across labs\",\n      \"pmids\": [\"22559944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SRGAP2C arose ~2.4 mya as a partial duplication encoding only the promoter and first nine exons of SRGAP2A, resulting in a truncated protein. Sequence and expression analyses indicate SRGAP2C is the most fixed human-specific duplicate and most likely to encode a functional protein that antagonizes parental SRGAP2A function immediately at birth.\",\n      \"method\": \"Genomic sequencing of haploid hydatidiform mole, comparative sequence analysis, expression analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genomic and expression analysis in single study; functional antagonism inferred from sequence but supported by companion paper\",\n      \"pmids\": [\"22559943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of SRGAP2A revealed it homodimerizes through a large interface including an F-BAR domain, a newly identified F-BAR extension (Fx), and RhoGAP-SH3 domains, with an unusual inverse geometry enabling associations with lamellipodia and dendritic spine heads. SRGAP2C carries a defective Fx-domain that severely compromises its solubility and membrane-scaffolding ability; SRGAP2A:SRGAP2C heterodimers form but are insoluble, thereby inhibiting SRGAP2A activity. The modern form of SRGAP2C (from ~2.4 mya) is more effective at heterodimerizing with SRGAP2A than the primal form.\",\n      \"method\": \"X-ray crystallography of SRGAP2A, in vitro heterodimerization assays, solubility assays, cell culture membrane-scaffolding assays, mutagenesis\",\n      \"journal\": \"Molecular biology and evolution\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determination plus in vitro reconstitution of dimerization and solubility assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"28333212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SRGAP2C and SRGAP2B are intrinsically unstable proteins in neurons; upon heterodimerization with SRGAP2A, they reduce SRGAP2A levels in a proteasome-dependent manner. SRGAP2C uniquely (compared to SRGAP2B) induces long-lasting changes in synaptic density throughout adulthood, due to specific non-synonymous mutations targeting arginine residues that enhance its ability to inhibit SRGAP2A and increase both excitatory and inhibitory synapse density with protracted maturation.\",\n      \"method\": \"Neuronal expression of SRGAP2B and SRGAP2C, proteasome inhibitor assays, heterodimerization assays, site-directed mutagenesis of arginine residues, synaptic density quantification across developmental stages\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteasome inhibition, mutagenesis, Co-IP, longitudinal synaptic assays) in single lab\",\n      \"pmids\": [\"31822692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRGAP2C expression in mice specifically increases local and long-range cortico-cortical connections onto layer 2/3 pyramidal neurons, shifts the fraction of layer 2/3 PNs activated by sensory stimulation, and enhances cortex-dependent sensory-discrimination learning. Computational modelling showed that increased layer 4 to layer 2/3 connectivity induced by SRGAP2C explains key changes in sensory coding.\",\n      \"method\": \"Transgenic mouse expression (all cortical PNs), viral circuit tracing, in vivo calcium imaging, sensory discrimination behavioral task, computational modelling\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal circuit and behavioral methods, replicated across multiple measures in single rigorous study\",\n      \"pmids\": [\"34707291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SRGAP2C enhances synaptic accumulation of CTNND2 (delta-catenin) in human neurons. CTNND2 was identified as a major binding partner of SRGAP2A/SRGAP2C and acts downstream to slow synaptic maturation; CTNND2 deficiency leads to synaptic loss of SYNGAP1. This pathway links human-specific SRGAP2C activity to synaptic neoteny via CTNND2 regulation.\",\n      \"method\": \"Co-immunoprecipitation (SRGAP2-CTNND2 interaction), loss-of-function of CTNND2 in neurons, quantification of synaptic CTNND2 accumulation in human neurons expressing SRGAP2C, synaptic maturation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and neuronal loss-of-function with synaptic readouts, single lab\",\n      \"pmids\": [\"39352808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In transgenic cynomolgus macaques carrying SRGAP2C, delayed brain development was observed with increased deep-layer neurons during fetal neurogenesis and delayed synaptic maturation in adolescence, alongside neotenic transcriptome expression in pathways related to neuron ensheathment, synaptic connections, extracellular matrix, and energy metabolism.\",\n      \"method\": \"Transgenic macaque generation, longitudinal MRI imaging, histological quantification of cortical neurons, transcriptome analysis, behavioral cognitive testing\",\n      \"journal\": \"National science review\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic primate model with multiple cellular and imaging readouts, single lab\",\n      \"pmids\": [\"38090550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In zebrafish, srgap2 knockout larvae phenocopy 'humanized' SRGAP2C-expressing larvae, including altered morphometric features, differential expression of synapse-, axonogenesis-, and vision-related genes, skewed excitatory/inhibitory neuron balance, seizure susceptibility, altered microglial membrane dynamics and delayed microglial maturation, and increased sensitivity to visual cues. Comparison of human (+SRGAP2C) vs. non-human primate (-SRGAP2C) transcriptomes in microglia showed overlapping gene alterations with zebrafish srgap2 mutants.\",\n      \"method\": \"Zebrafish srgap2 knockout, SRGAP2C transgenic zebrafish, single-cell RNA sequencing, behavioral seizure assays, live microglial imaging, visual sensitivity assays, cross-species transcriptome comparison\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (scRNA-seq, live imaging, behavioral assays) in zebrafish model, preprint not yet peer-reviewed\",\n      \"pmids\": [\"39314374\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A massively parallel reporter assay identified differentially active cis-regulatory elements (CREs) within the SRGAP2C locus that may contribute to paralog-specific expression patterns. Validated CREs for SRGAP2C showed differential activity compared to the ancestral chimpanzee ortholog, suggesting regulatory divergence contributes moderately to SRGAP2C-specific expression.\",\n      \"method\": \"Massively parallel reporter assay (MPRA) in lymphoblastoid and neuroblastoma cell lines, long-read expression and epigenomic data, CRE validation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — reporter assay establishes CRE activity but functional consequence for SRGAP2C protein is inferred; preprint, single lab\",\n      \"pmids\": [\"41292788\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SRGAP2C is a human-specific truncated paralog of SRGAP2A that encodes a defective F-BAR/Fx domain protein; it heterodimerizes with full-length SRGAP2A, forming insoluble complexes that inhibit SRGAP2A function and reduce its levels via proteasome-dependent degradation, thereby increasing excitatory and inhibitory synapse density, prolonging synapse maturation (neoteny), enhancing cortico-cortical connectivity, and promoting accumulation of the synaptic regulator CTNND2 — collectively contributing to human-specific features of neocortical development and circuit function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRGAP2C is a human-specific, partially duplicated paralog of SRGAP2A that arose ~2.4 mya and encodes a truncated F-BAR domain protein which acts as a dominant antagonist of its ancestral parent, contributing to human-specific features of neocortical development [#0, #1]. The duplication retained only the promoter and first nine exons of SRGAP2A, producing a protein with a defective F-BAR extension (Fx) domain that is poorly soluble and unable to scaffold membranes; SRGAP2C nonetheless heterodimerizes with full-length SRGAP2A through the F-BAR/Fx and RhoGAP-SH3 interface, and the resulting heterodimers are insoluble and functionally inhibitory [#2]. In neurons SRGAP2C is intrinsically unstable, and upon heterodimerization it reduces SRGAP2A levels in a proteasome-dependent manner; human-specific arginine substitutions enhance this inhibitory capacity and drive long-lasting increases in both excitatory and inhibitory synapse density with protracted (neotenic) maturation [#3]. Functionally, expression of SRGAP2C in mouse cortex phenocopies SRGAP2 deficiency — sustained radial migration, neotenic spine maturation, and increased density of longer spines [#0] — and specifically increases local and long-range cortico-cortical connectivity onto layer 2/3 pyramidal neurons, reshaping sensory coding and enhancing sensory-discrimination learning [#4]. Downstream, SRGAP2C enhances synaptic accumulation of its binding partner CTNND2 (delta-catenin), which slows synaptic maturation and supports synaptic SYNGAP1 retention, linking SRGAP2C activity to synaptic neoteny [#5]. Transgenic primate and zebrafish models reproduce delayed neurodevelopment and neotenic transcriptomic and circuit phenotypes [#6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that SRGAP2C is not a pseudogene but a functional human-specific paralog that antagonizes ancestral SRGAP2A, answering whether the duplication had a biological consequence for cortical development.\",\n      \"evidence\": \"Transgenic mouse neocortical expression, reciprocal Co-IP for dimerization, and neuronal morphology assays compared against SRGAP2 loss-of-function\",\n      \"pmids\": [\"22559944\", \"22559943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The structural basis for how a truncated protein inhibits the full-length parent was not resolved\",\n        \"Whether inhibition occurs by sequestration, degradation, or steric block was undefined\",\n        \"Synaptic and circuit-level consequences in adult cortex were not addressed\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the molecular mechanism of antagonism by showing SRGAP2A homodimerizes through an F-BAR/Fx/RhoGAP-SH3 interface and that SRGAP2C's defective Fx domain produces insoluble, non-functional heterodimers.\",\n      \"evidence\": \"X-ray crystallography of SRGAP2A plus in vitro heterodimerization, solubility, membrane-scaffolding, and mutagenesis assays\",\n      \"pmids\": [\"28333212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not establish how insoluble heterodimers are handled in neurons (e.g. degradation)\",\n        \"No structure of the SRGAP2A:SRGAP2C heterodimer itself\",\n        \"Link between solubility defect and synaptic phenotype remained indirect\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected heterodimerization to a degradative outcome and identified the specific arginine substitutions that make SRGAP2C a more potent and durable inhibitor than the paralog SRGAP2B.\",\n      \"evidence\": \"Neuronal expression of SRGAP2B/2C, proteasome inhibitor assays, site-directed mutagenesis of arginine residues, and longitudinal synaptic density quantification\",\n      \"pmids\": [\"31822692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The E3 ligase and recognition pathway targeting SRGAP2A for degradation were not identified\",\n        \"How proteasomal turnover translates to sustained adult synaptic changes was not mechanistically traced\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that SRGAP2C reshapes cortical circuit architecture and behavior, moving beyond single-cell morphology to network-level function.\",\n      \"evidence\": \"Transgenic mouse expression in cortical pyramidal neurons with viral tracing, in vivo calcium imaging, sensory-discrimination behavior, and computational modelling\",\n      \"pmids\": [\"34707291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular intermediary linking SRGAP2A inhibition to specific connectivity changes was not identified\",\n        \"Results obtained in mouse cortex; primate-specific effects untested here\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified CTNND2 as a downstream synaptic effector, defining a molecular pathway from SRGAP2C to synaptic neoteny.\",\n      \"evidence\": \"Co-IP mapping the SRGAP2-CTNND2 interaction, CTNND2 loss-of-function in neurons, and quantification of synaptic CTNND2 accumulation in human neurons expressing SRGAP2C\",\n      \"pmids\": [\"39352808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CTNND2 accumulation is necessary for all SRGAP2C circuit phenotypes was not established\",\n        \"The mechanism by which reduced SRGAP2A increases synaptic CTNND2 was not fully resolved\",\n        \"Single lab, reciprocal Co-IP without orthogonal interaction validation\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended SRGAP2C's developmental effects to a primate model, testing whether the gene drives neotenic phenotypes in a brain closer to human.\",\n      \"evidence\": \"Transgenic cynomolgus macaque generation with longitudinal MRI, histological neuron quantification, transcriptomics, and cognitive testing\",\n      \"pmids\": [\"38090550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal link between transcriptomic neoteny and behavioral outcomes not established\",\n        \"Small cohort inherent to transgenic primate studies\",\n        \"Cell-type-specific mechanism in macaque cortex not dissected\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed via zebrafish that loss of srgap2 and gain of SRGAP2C converge on shared phenotypes, including microglial and excitatory/inhibitory balance changes, broadening the cellular scope beyond pyramidal neurons.\",\n      \"evidence\": \"Zebrafish srgap2 knockout and SRGAP2C transgenics with scRNA-seq, live microglial imaging, behavioral seizure and visual assays, and cross-species transcriptome comparison (preprint)\",\n      \"pmids\": [\"39314374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint, not yet peer-reviewed\",\n        \"Microglial effects of SRGAP2C in mammalian systems not confirmed\",\n        \"Whether zebrafish phenotypes reflect the same molecular antagonism mechanism is inferred\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Began addressing how SRGAP2C achieves paralog-specific expression by identifying differentially active cis-regulatory elements within the locus.\",\n      \"evidence\": \"Massively parallel reporter assay in lymphoblastoid and neuroblastoma lines with long-read expression/epigenomic data and CRE validation (preprint)\",\n      \"pmids\": [\"41292788\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Reporter activity establishes CRE function but consequence for endogenous SRGAP2C protein is inferred; preprint, single lab\",\n        \"No demonstration that the CREs control native SRGAP2C levels in neurons\",\n        \"Regulatory contribution quantified only as moderate\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The E3 ligase and degradation machinery that clear SRGAP2A:SRGAP2C heterodimers, and whether CTNND2 accumulation is required for SRGAP2C's circuit-level and behavioral effects, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No identified ubiquitin ligase for proteasome-dependent SRGAP2A reduction\",\n        \"Necessity of CTNND2 for connectivity and behavioral phenotypes untested\",\n        \"Structure of the inhibitory heterodimer not determined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"complexes\": [\n      \"SRGAP2A:SRGAP2C heterodimer\"\n    ],\n    \"partners\": [\n      \"SRGAP2A\",\n      \"CTNND2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}