{"gene":"SEMA5A","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":1999,"finding":"The PDZ-containing neural protein SEMCAP-1 (also known as GIPC) binds the cytoplasmic C-terminal four residues (ESSV) of M-SemF (SEMA5A) via its single PDZ domain. Co-expression of SEMCAP-1/GIPC redistributes dispersed M-SemF into detergent-resistant aggregates in HEK293 cells, indicating that SEMCAP-1/GIPC regulates the subcellular distribution of SEMA5A on the cell surface. SEMCAP-2 is a closely related nonneuronal binding partner with the same interaction. M-SemF does not interact with other class I PDZ proteins, and SEMCAP-1 does not interact with other class I PDZ-binding motif proteins, indicating specificity.","method":"Yeast two-hybrid identification of SEMCAP-1/GIPC as M-SemF cytoplasmic domain-associated protein; co-expression in HEK293 cells with fluorescence/detergent-resistance assay; mutagenesis of PDZ domain and C-terminal residues","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding validation and functional redistribution assay in HEK293 cells, single lab, two orthogonal methods (pulldown + cell redistribution)","pmids":["10318831"],"is_preprint":false},{"year":2003,"finding":"Sema5A is expressed by neuroepithelial cells surrounding retinal axons at the optic disc and along the optic nerve. Sema5A triggers an invariant inhibitory (collapse/repulsive) response in retinal axon growth cones regardless of co-exposure to L1, laminin, or netrin-1 signaling. Antibody perturbation of Sema5A function in living embryo preparations caused retinal axons to stray outside the optic nerve bundle, demonstrating that Sema5A normally acts as an inhibitory ensheathing cue to maintain integrity of the retinal axon pathway.","method":"In situ hybridization and immunohistochemistry for localization; growth cone collapse assay, substratum choice assay, and neurite outgrowth assay in vitro; function-blocking antibody perturbation in ex vivo living embryo preparations","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro assays plus in vivo antibody perturbation with defined axon pathfinding phenotype, replicated across several assay formats in one rigorous study","pmids":["12506007"],"is_preprint":false},{"year":2004,"finding":"Sema5A is selectively expressed by oligodendrocytes and their precursors (not astrocytes) in the optic nerve. Sema5A presented as a substrate induces growth cone collapse and inhibits axon elongation by retinal ganglion cells (RGCs) in vitro. A neutralizing antibody against Sema5A significantly increased RGC axon growth on postnatal and adult optic nerve explants, indicating that oligodendrocyte-derived Sema5A contributes to the inhibitory glial environment that prevents CNS axon regeneration.","method":"Purified glial cell RNA analysis; substrate-bound Sema5A growth cone collapse assay and neurite outgrowth assay with RGCs; neutralizing antibody application to optic nerve explant cultures with axon growth quantification","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (collapse assay, substrate inhibition, antibody neutralization on explants), single lab but rigorous with multiple independent readouts","pmids":["15163691"],"is_preprint":false},{"year":2005,"finding":"Genetic ablation of Sema5a in mice (null mutation) results in embryonic lethality between E11.5 and E12.5. Null mutant embryos display defective remodeling of cranial blood vessels, with decreased complexity of hierarchically organized branches of cranial cardinal veins, identifying a required role for Sema5A in regional patterning of the cranial vasculature during embryonic development.","method":"Targeted gene knockout in mice; embryo morphological analysis; vascular analysis of cranial cardinal vein branching complexity","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function in vivo with specific vascular phenotype, rigorous histological analysis, first class-5 semaphorin knockout study","pmids":["15743826"],"is_preprint":false},{"year":2021,"finding":"The thrombospondin repeat (TSP1) domain of SEMA5A is essential for its pro-angiogenic function in rheumatoid arthritis pathogenesis. SEMA5A promotes fibroblast-like synoviocyte (FLS) proliferation and angiogenesis in vitro (chicken embryo allantoic membrane and tube formation assays). Treatment with SEMA5A-neutralizing monoclonal antibodies attenuated joint injury and inflammation in a collagen-induced arthritis (CIA) mouse model. Rescue of TSP1-deleted SEMA5A in Sema5a-/- CIA mice failed to reduce arthritis severity, confirming TSP1 as the functionally essential domain for pannus formation.","method":"Transcriptome sequencing of SEMA5A-transfected FLSs; MTT proliferation assay; chicken embryo allantoic membrane angiogenesis assay; tube formation assay; SEMA5A-mAb treatment in CIA mouse model; domain-deletion rescue experiment in Sema5a-/- CIA mice","journal":"Rheumatology (Oxford, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-deletion rescue experiment in vivo plus multiple orthogonal in vitro angiogenesis assays and in vivo antibody treatment, multiple methods across in vitro and in vivo settings","pmids":["33616619"],"is_preprint":false},{"year":2023,"finding":"The ASD-associated Sema5A mutations R676C and S951C localize Sema5A protein around the plasma membrane and promote excessive neurite-like process elongation in N1E-115 neuronal cells. R676C strongly activates c-Jun N-terminal kinase (JNK) signaling. The excessive process elongation was partially neutralized by a Plexin-B3-blocking antibody (indicating autocrine signaling through its receptor) and was recovered by a chemical JNK inhibitor or by blocking RhoG-Elmo1 interaction upstream of JNK.","method":"Expression of mutant Sema5A constructs in N1E-115 cells; confocal immunofluorescence localization; neurite length measurement; JNK activity assay; Plexin-B3 neutralizing antibody; chemical JNK inhibitor treatment; inhibitory Elmo1 RhoG-binding domain construct","journal":"Pathophysiology : the official journal of the International Society for Pathophysiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and genetic tools in a cell model, single lab, mechanistic pathway placement via rescue experiments","pmids":["38133141"],"is_preprint":false},{"year":2023,"finding":"M2-type tumor-associated macrophage (TAM)-derived SEMA5A binds its receptor PLXNB3 expressed on pancreatic adenocarcinoma (PDAC) tumor cells. The SEMA5A-PLXNB3 axis promotes tumor cell proliferation and survival by enhancing aerobic glycolysis (Warburg effect) in PDAC liver metastasis.","method":"Liver metastasis patient samples; intrasplenic injection mouse models; KPC (KrasG12D/Trp53R172H/Pdx1-Cre) mouse models; receptor-ligand interaction studies; glycolysis assays","journal":"Journal of immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse models and patient samples with identified receptor-ligand pair and metabolic mechanism, single lab","pmids":["36741230"],"is_preprint":false},{"year":2025,"finding":"The ASD- and intellectual disability-associated Sema5A p.Arg676Cys variant drives excessive neuronal process elongation through the ErbB2-Dock7 signaling axis. Knockdown of Dock7 by shRNA or inhibition of ErbB2 kinase reduced excessive process elongation in primary cortical neurons and N1E-115 cells. This pathway specifically mediates overactivation of the downstream Rho GTPases Rac1 and Cdc42.","method":"shRNA knockdown of Dock7 in primary cortical neurons and N1E-115 cells; ErbB2 kinase chemical inhibition; Rac1 and Cdc42 activity assays; neurite length measurement","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown and pharmacological inhibition with downstream GTPase readouts in two cell systems, single lab","pmids":["41226692"],"is_preprint":false},{"year":2026,"finding":"The ASD-linked Sema5A p.Arg676Cys mutation drives excessive neuronal process elongation through the Arf6/FE65/ELMO2 signalosome, which elevates Rac1 activity. CRISPR/Cas13-mediated knockdown of Arf6 or FE65 reversed excessively elongated processes in primary cortical neurons. Expression of the ELMO2-binding domain of FE65 restored Rac1 activity required for process elongation, placing FE65 as a specific coupler between Sema5A p.Arg676Cys and the ELMO2-Rac1 signaling cascade.","method":"CRISPR/Cas13 knockdown of Arf6 and FE65 in primary cortical neurons and N1E-115 cells; expression of ELMO2-binding domain of FE65; Rac1 activity assay; neurite length measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR/Cas13 knockdown with rescue construct and downstream Rac1 activity readout in two cell systems, single lab","pmids":["41703006"],"is_preprint":false},{"year":2019,"finding":"FUS directly binds Sema5a mRNA and regulates its expression in a FUS-dose-dependent manner. In FUS transgenic mice overexpressing wild-type human FUS, Sema5a expression is reduced; this is accompanied by age-dependent decreases in hippocampal spine density and long-term potentiation, and hippocampus-dependent cognitive deficits.","method":"Transcriptomic analysis of FUS transgenic mouse brain; RNA immunoprecipitation (FUS binding to Sema5a mRNA); hippocampal electrophysiology (LTP); spine density measurement","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding shown with RIP, dose-dependent expression regulation, and in vivo functional phenotype in transgenic mice, single lab","pmids":["31509188"],"is_preprint":false}],"current_model":"SEMA5A (M-SemF/semF) is a transmembrane semaphorin that acts as an axon guidance cue: it signals through its receptor Plexin-B3 to inhibit growth cone advance and ensheath axon pathways during CNS development, with its cytoplasmic C-terminal ESSV motif binding the PDZ protein SEMCAP-1/GIPC to regulate its surface distribution; its TSP1 domain is required for pro-angiogenic and pro-inflammatory activity in rheumatoid arthritis; ASD-associated gain-of-function mutations (R676C, S951C) drive excessive neuronal process elongation via JNK/RhoG-Elmo1, ErbB2-Dock7-Rac1/Cdc42, and Arf6/FE65/ELMO2-Rac1 signaling cascades; M2 macrophage-secreted SEMA5A signals through tumor-cell PLXNB3 to enhance the Warburg effect in PDAC metastasis; and Sema5a knockout mice die at E11.5–E12.5 with defective cranial vascular remodeling, establishing an essential developmental role in vascular patterning."},"narrative":{"mechanistic_narrative":"SEMA5A (M-SemF) is a transmembrane class-5 semaphorin that functions as a bifunctional axon guidance cue and a regulator of vascular and neuronal patterning during development [PMID:12506007, PMID:15743826]. As an inhibitory ensheathing cue, Sema5A is expressed by neuroepithelial cells and oligodendrocytes flanking developing axon tracts, where it triggers growth cone collapse and restrains axon elongation to maintain pathway integrity, and contributes to the inhibitory glial environment that limits CNS axon regeneration [PMID:12506007, PMID:15163691]. Its short cytoplasmic C-terminal ESSV motif binds the single PDZ domain of SEMCAP-1/GIPC, which redistributes the protein into detergent-resistant surface aggregates and thereby controls its subcellular distribution [PMID:10318831]. Genetic ablation in mice is embryonic lethal at E11.5–E12.5 with defective remodeling of cranial vasculature, establishing an essential role in vascular patterning [PMID:15743826], and its thrombospondin (TSP1) repeat domain is required for pro-angiogenic, pro-inflammatory activity driving pannus formation in rheumatoid arthritis [PMID:33616619]. SEMA5A also acts non-cell-autonomously in cancer: M2 macrophage-derived SEMA5A engages tumor-cell PLXNB3 to enhance aerobic glycolysis and promote pancreatic adenocarcinoma liver metastasis [PMID:36741230]. Autism-spectrum-disorder-associated gain-of-function variants (R676C, S951C) drive excessive neuronal process elongation through autocrine Plexin-B3 signaling that converges on Rho-family GTPase activation via JNK/RhoG-Elmo1, ErbB2-Dock7-Rac1/Cdc42, and Arf6/FE65/ELMO2-Rac1 cascades [PMID:38133141, PMID:41226692, PMID:41703006].","teleology":[{"year":1999,"claim":"Established how the cytoplasmic tail of SEMA5A is read out intracellularly, identifying a PDZ-domain adaptor that controls receptor surface organization.","evidence":"Yeast two-hybrid, HEK293 co-expression with detergent-resistance/fluorescence assay, and PDZ/C-terminal mutagenesis","pmids":["10318831"],"confidence":"Medium","gaps":["Functional consequence of GIPC-mediated clustering for in vivo signaling not tested","No link to a specific receptor or downstream pathway established here"]},{"year":2003,"claim":"Defined SEMA5A as an inhibitory ensheathing guidance cue, showing it produces an invariant repulsive growth cone response that confines retinal axons to their pathway in vivo.","evidence":"In situ/IHC localization, growth cone collapse and outgrowth assays, and function-blocking antibody perturbation in ex vivo embryo preparations","pmids":["12506007"],"confidence":"High","gaps":["Receptor mediating the inhibitory response not identified","Bifunctional context-dependence (attractive vs repulsive) not resolved"]},{"year":2004,"claim":"Extended the inhibitory role to glia, showing oligodendrocyte-derived SEMA5A contributes to the non-permissive environment limiting CNS axon regeneration.","evidence":"Glial RNA analysis, substrate-bound collapse and outgrowth assays with RGCs, and neutralizing antibody on optic nerve explants","pmids":["15163691"],"confidence":"High","gaps":["Receptor and intracellular signaling in RGCs not identified","Relevance to in vivo regeneration after injury not tested"]},{"year":2005,"claim":"Demonstrated an essential, non-neuronal developmental requirement by showing SEMA5A loss causes embryonic lethality with defective cranial vascular remodeling.","evidence":"Targeted knockout in mice with embryo morphology and cranial vein branching analysis","pmids":["15743826"],"confidence":"High","gaps":["Receptor and effector pathway in vascular cells not defined","Whether vascular and axonal roles use shared signaling unknown"]},{"year":2019,"claim":"Placed Sema5a as a downstream target of an RNA-binding regulator, linking its dose to synaptic plasticity and cognition.","evidence":"FUS transgenic mouse transcriptomics, RNA immunoprecipitation, hippocampal LTP and spine density measurement","pmids":["31509188"],"confidence":"Medium","gaps":["Direct causal contribution of reduced Sema5a to the cognitive phenotype not isolated","Mechanism linking surface SEMA5A to spine density not established"]},{"year":2021,"claim":"Identified the TSP1 domain as the functionally essential module for SEMA5A pro-angiogenic and pro-inflammatory activity in arthritis pathogenesis.","evidence":"FLS transcriptomics, proliferation and angiogenesis assays, anti-SEMA5A mAb in CIA mice, and TSP1-deletion rescue in Sema5a-/- CIA mice","pmids":["33616619"],"confidence":"High","gaps":["Receptor engaged by the TSP1 domain in synoviocytes/endothelium not defined","Downstream angiogenic signaling pathway not mapped"]},{"year":2023,"claim":"Established a non-cell-autonomous oncogenic axis in which macrophage-derived SEMA5A signals through tumor PLXNB3 to reprogram metabolism in metastasis.","evidence":"PDAC patient samples, intrasplenic injection and KPC mouse models, receptor-ligand studies, and glycolysis assays","pmids":["36741230"],"confidence":"Medium","gaps":["Molecular link between PLXNB3 engagement and glycolytic enzymes not detailed","Reciprocal/structural validation of the SEMA5A-PLXNB3 interaction limited"]},{"year":2023,"claim":"Showed ASD-associated SEMA5A gain-of-function variants drive aberrant neurite elongation via autocrine Plexin-B3 signaling converging on JNK through RhoG-Elmo1.","evidence":"Mutant Sema5A expression in N1E-115 cells, confocal localization, JNK activity assay, Plexin-B3 blocking antibody, JNK inhibitor, and Elmo1 RhoG-binding domain construct","pmids":["38133141"],"confidence":"Medium","gaps":["Mechanism by which point mutations create gain-of-function not resolved","Confined to cell-line model; in vivo relevance not tested"]},{"year":2025,"claim":"Resolved a second effector branch for the R676C variant, identifying the ErbB2-Dock7 axis as a driver of Rac1/Cdc42 overactivation underlying excessive elongation.","evidence":"shRNA knockdown of Dock7, ErbB2 kinase inhibition, and Rac1/Cdc42 activity assays in primary cortical neurons and N1E-115 cells","pmids":["41226692"],"confidence":"Medium","gaps":["How SEMA5A/Plexin-B3 engages ErbB2 mechanistically not defined","Relationship between this branch and the JNK/RhoG branch not integrated"]},{"year":2026,"claim":"Defined a third converging branch in which R676C signals through an Arf6/FE65/ELMO2 signalosome to elevate Rac1, with FE65 as the specific coupler.","evidence":"CRISPR/Cas13 knockdown of Arf6 and FE65, ELMO2-binding domain rescue, and Rac1 activity assay in primary cortical neurons and N1E-115 cells","pmids":["41703006"],"confidence":"Medium","gaps":["How multiple parallel cascades (JNK, ErbB2-Dock7, Arf6-FE65) are coordinated unknown","In vivo confirmation in ASD models lacking"]},{"year":null,"claim":"How SEMA5A's shared structural elements (TSP1 domain, ESSV/GIPC tail) and receptor (Plexin-B3) are deployed across its distinct roles in axon guidance, vascular patterning, angiogenic inflammation, and tumor metabolism remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying receptor/effector framework connecting developmental, inflammatory, and oncogenic contexts","Structural basis for ligand-receptor engagement uncharacterized in the corpus","Mechanism distinguishing inhibitory (guidance) from elongation-promoting (mutant) outputs unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,2,6]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,7,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,7,8]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["GIPC1","PLXNB3","DOCK7","ERBB2","ARF6","APBB1","ELMO2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13591","full_name":"Semaphorin-5A","aliases":["Semaphorin-F","Sema F"],"length_aa":1074,"mass_kda":120.6,"function":"Bifunctional axonal guidance cue regulated by sulfated proteoglycans; attractive effects result from interactions with heparan sulfate proteoglycans (HSPGs), while the inhibitory effects depend on interactions with chondroitin sulfate proteoglycans (CSPGs) (By similarity). Ligand for receptor PLXNB3. In glioma cells, SEMA5A stimulation of PLXNB3 results in the disassembly of F-actin stress fibers, disruption of focal adhesions and cellular collapse as well as inhibition of cell migration and invasion through ARHGDIA-mediated inactivation of RAC1. May promote angiogenesis by increasing endothelial cell proliferation and migration and inhibiting apoptosis","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q13591/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEMA5A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SEMA5A","total_profiled":1310},"omim":[{"mim_id":"613608","title":"EPILEPSY, FAMILIAL ADULT MYOCLONIC, 3; FAME3","url":"https://www.omim.org/entry/613608"},{"mim_id":"609907","title":"SEMAPHORIN 3D; SEMA3D","url":"https://www.omim.org/entry/609907"},{"mim_id":"609297","title":"SEMAPHORIN 5A; SEMA5A","url":"https://www.omim.org/entry/609297"},{"mim_id":"300214","title":"PLEXIN B3; PLXNB3","url":"https://www.omim.org/entry/300214"},{"mim_id":"209850","title":"AUTISM","url":"https://www.omim.org/entry/209850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEMA5A"},"hgnc":{"alias_symbol":["semF"],"prev_symbol":["SEMAF"]},"alphafold":{"accession":"Q13591","domains":[{"cath_id":"2.20.100.10","chopping":"842-889","consensus_level":"medium","plddt":78.8033,"start":842,"end":889}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13591","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13591-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13591-F1-predicted_aligned_error_v6.png","plddt_mean":77.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEMA5A","jax_strain_url":"https://www.jax.org/strain/search?query=SEMA5A"},"sequence":{"accession":"Q13591","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13591.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13591/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13591"}},"corpus_meta":[{"pmid":"20802022","id":"PMC_20802022","title":"Identification of a 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report.","date":"2022","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36451418","citation_count":1,"is_preprint":false},{"pmid":"38294620","id":"PMC_38294620","title":"lncRNA TTTY14 participates in the progression of repeated implantation failure by regulating the miR-6088/SEMA5A axis.","date":"2024","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38294620","citation_count":0,"is_preprint":false},{"pmid":"41703006","id":"PMC_41703006","title":"Autism spectrum disorder-associated Sema5A p.Arg676Cys drives Arf6/FE65 signaling and aberrant cell morphogenesis.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41703006","citation_count":0,"is_preprint":false},{"pmid":"41204460","id":"PMC_41204460","title":"Clinical significance of serum Sema5A and IGFBP-3 in type 2 diabetes mellitus with hyperthyroidism.","date":"2025","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41204460","citation_count":0,"is_preprint":false},{"pmid":"41226692","id":"PMC_41226692","title":"The ErbB2-Dock7 Signaling Axis Mediates Excessive Cell Morphogenesis Induced by Autism Spectrum Disorder- and Intellectual Disability-Associated Sema5A p.Arg676Cys.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41226692","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.28.25334434","title":"Circulating transcriptional biomarkers serve as surrogates of disease progression in Charcot-Marie-Tooth 1A disease","date":"2025-09-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.28.25334434","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17300,"output_tokens":3429,"usd":0.051667,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10965,"output_tokens":3663,"usd":0.0732,"stage2_stop_reason":"end_turn"},"total_usd":0.124867,"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\": 1999,\n      \"finding\": \"The PDZ-containing neural protein SEMCAP-1 (also known as GIPC) binds the cytoplasmic C-terminal four residues (ESSV) of M-SemF (SEMA5A) via its single PDZ domain. Co-expression of SEMCAP-1/GIPC redistributes dispersed M-SemF into detergent-resistant aggregates in HEK293 cells, indicating that SEMCAP-1/GIPC regulates the subcellular distribution of SEMA5A on the cell surface. SEMCAP-2 is a closely related nonneuronal binding partner with the same interaction. M-SemF does not interact with other class I PDZ proteins, and SEMCAP-1 does not interact with other class I PDZ-binding motif proteins, indicating specificity.\",\n      \"method\": \"Yeast two-hybrid identification of SEMCAP-1/GIPC as M-SemF cytoplasmic domain-associated protein; co-expression in HEK293 cells with fluorescence/detergent-resistance assay; mutagenesis of PDZ domain and C-terminal residues\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding validation and functional redistribution assay in HEK293 cells, single lab, two orthogonal methods (pulldown + cell redistribution)\",\n      \"pmids\": [\"10318831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Sema5A is expressed by neuroepithelial cells surrounding retinal axons at the optic disc and along the optic nerve. Sema5A triggers an invariant inhibitory (collapse/repulsive) response in retinal axon growth cones regardless of co-exposure to L1, laminin, or netrin-1 signaling. Antibody perturbation of Sema5A function in living embryo preparations caused retinal axons to stray outside the optic nerve bundle, demonstrating that Sema5A normally acts as an inhibitory ensheathing cue to maintain integrity of the retinal axon pathway.\",\n      \"method\": \"In situ hybridization and immunohistochemistry for localization; growth cone collapse assay, substratum choice assay, and neurite outgrowth assay in vitro; function-blocking antibody perturbation in ex vivo living embryo preparations\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro assays plus in vivo antibody perturbation with defined axon pathfinding phenotype, replicated across several assay formats in one rigorous study\",\n      \"pmids\": [\"12506007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Sema5A is selectively expressed by oligodendrocytes and their precursors (not astrocytes) in the optic nerve. Sema5A presented as a substrate induces growth cone collapse and inhibits axon elongation by retinal ganglion cells (RGCs) in vitro. A neutralizing antibody against Sema5A significantly increased RGC axon growth on postnatal and adult optic nerve explants, indicating that oligodendrocyte-derived Sema5A contributes to the inhibitory glial environment that prevents CNS axon regeneration.\",\n      \"method\": \"Purified glial cell RNA analysis; substrate-bound Sema5A growth cone collapse assay and neurite outgrowth assay with RGCs; neutralizing antibody application to optic nerve explant cultures with axon growth quantification\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (collapse assay, substrate inhibition, antibody neutralization on explants), single lab but rigorous with multiple independent readouts\",\n      \"pmids\": [\"15163691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Genetic ablation of Sema5a in mice (null mutation) results in embryonic lethality between E11.5 and E12.5. Null mutant embryos display defective remodeling of cranial blood vessels, with decreased complexity of hierarchically organized branches of cranial cardinal veins, identifying a required role for Sema5A in regional patterning of the cranial vasculature during embryonic development.\",\n      \"method\": \"Targeted gene knockout in mice; embryo morphological analysis; vascular analysis of cranial cardinal vein branching complexity\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function in vivo with specific vascular phenotype, rigorous histological analysis, first class-5 semaphorin knockout study\",\n      \"pmids\": [\"15743826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The thrombospondin repeat (TSP1) domain of SEMA5A is essential for its pro-angiogenic function in rheumatoid arthritis pathogenesis. SEMA5A promotes fibroblast-like synoviocyte (FLS) proliferation and angiogenesis in vitro (chicken embryo allantoic membrane and tube formation assays). Treatment with SEMA5A-neutralizing monoclonal antibodies attenuated joint injury and inflammation in a collagen-induced arthritis (CIA) mouse model. Rescue of TSP1-deleted SEMA5A in Sema5a-/- CIA mice failed to reduce arthritis severity, confirming TSP1 as the functionally essential domain for pannus formation.\",\n      \"method\": \"Transcriptome sequencing of SEMA5A-transfected FLSs; MTT proliferation assay; chicken embryo allantoic membrane angiogenesis assay; tube formation assay; SEMA5A-mAb treatment in CIA mouse model; domain-deletion rescue experiment in Sema5a-/- CIA mice\",\n      \"journal\": \"Rheumatology (Oxford, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-deletion rescue experiment in vivo plus multiple orthogonal in vitro angiogenesis assays and in vivo antibody treatment, multiple methods across in vitro and in vivo settings\",\n      \"pmids\": [\"33616619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The ASD-associated Sema5A mutations R676C and S951C localize Sema5A protein around the plasma membrane and promote excessive neurite-like process elongation in N1E-115 neuronal cells. R676C strongly activates c-Jun N-terminal kinase (JNK) signaling. The excessive process elongation was partially neutralized by a Plexin-B3-blocking antibody (indicating autocrine signaling through its receptor) and was recovered by a chemical JNK inhibitor or by blocking RhoG-Elmo1 interaction upstream of JNK.\",\n      \"method\": \"Expression of mutant Sema5A constructs in N1E-115 cells; confocal immunofluorescence localization; neurite length measurement; JNK activity assay; Plexin-B3 neutralizing antibody; chemical JNK inhibitor treatment; inhibitory Elmo1 RhoG-binding domain construct\",\n      \"journal\": \"Pathophysiology : the official journal of the International Society for Pathophysiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and genetic tools in a cell model, single lab, mechanistic pathway placement via rescue experiments\",\n      \"pmids\": [\"38133141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"M2-type tumor-associated macrophage (TAM)-derived SEMA5A binds its receptor PLXNB3 expressed on pancreatic adenocarcinoma (PDAC) tumor cells. The SEMA5A-PLXNB3 axis promotes tumor cell proliferation and survival by enhancing aerobic glycolysis (Warburg effect) in PDAC liver metastasis.\",\n      \"method\": \"Liver metastasis patient samples; intrasplenic injection mouse models; KPC (KrasG12D/Trp53R172H/Pdx1-Cre) mouse models; receptor-ligand interaction studies; glycolysis assays\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse models and patient samples with identified receptor-ligand pair and metabolic mechanism, single lab\",\n      \"pmids\": [\"36741230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The ASD- and intellectual disability-associated Sema5A p.Arg676Cys variant drives excessive neuronal process elongation through the ErbB2-Dock7 signaling axis. Knockdown of Dock7 by shRNA or inhibition of ErbB2 kinase reduced excessive process elongation in primary cortical neurons and N1E-115 cells. This pathway specifically mediates overactivation of the downstream Rho GTPases Rac1 and Cdc42.\",\n      \"method\": \"shRNA knockdown of Dock7 in primary cortical neurons and N1E-115 cells; ErbB2 kinase chemical inhibition; Rac1 and Cdc42 activity assays; neurite length measurement\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown and pharmacological inhibition with downstream GTPase readouts in two cell systems, single lab\",\n      \"pmids\": [\"41226692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The ASD-linked Sema5A p.Arg676Cys mutation drives excessive neuronal process elongation through the Arf6/FE65/ELMO2 signalosome, which elevates Rac1 activity. CRISPR/Cas13-mediated knockdown of Arf6 or FE65 reversed excessively elongated processes in primary cortical neurons. Expression of the ELMO2-binding domain of FE65 restored Rac1 activity required for process elongation, placing FE65 as a specific coupler between Sema5A p.Arg676Cys and the ELMO2-Rac1 signaling cascade.\",\n      \"method\": \"CRISPR/Cas13 knockdown of Arf6 and FE65 in primary cortical neurons and N1E-115 cells; expression of ELMO2-binding domain of FE65; Rac1 activity assay; neurite length measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR/Cas13 knockdown with rescue construct and downstream Rac1 activity readout in two cell systems, single lab\",\n      \"pmids\": [\"41703006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FUS directly binds Sema5a mRNA and regulates its expression in a FUS-dose-dependent manner. In FUS transgenic mice overexpressing wild-type human FUS, Sema5a expression is reduced; this is accompanied by age-dependent decreases in hippocampal spine density and long-term potentiation, and hippocampus-dependent cognitive deficits.\",\n      \"method\": \"Transcriptomic analysis of FUS transgenic mouse brain; RNA immunoprecipitation (FUS binding to Sema5a mRNA); hippocampal electrophysiology (LTP); spine density measurement\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding shown with RIP, dose-dependent expression regulation, and in vivo functional phenotype in transgenic mice, single lab\",\n      \"pmids\": [\"31509188\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEMA5A (M-SemF/semF) is a transmembrane semaphorin that acts as an axon guidance cue: it signals through its receptor Plexin-B3 to inhibit growth cone advance and ensheath axon pathways during CNS development, with its cytoplasmic C-terminal ESSV motif binding the PDZ protein SEMCAP-1/GIPC to regulate its surface distribution; its TSP1 domain is required for pro-angiogenic and pro-inflammatory activity in rheumatoid arthritis; ASD-associated gain-of-function mutations (R676C, S951C) drive excessive neuronal process elongation via JNK/RhoG-Elmo1, ErbB2-Dock7-Rac1/Cdc42, and Arf6/FE65/ELMO2-Rac1 signaling cascades; M2 macrophage-secreted SEMA5A signals through tumor-cell PLXNB3 to enhance the Warburg effect in PDAC metastasis; and Sema5a knockout mice die at E11.5–E12.5 with defective cranial vascular remodeling, establishing an essential developmental role in vascular patterning.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEMA5A (M-SemF) is a transmembrane class-5 semaphorin that functions as a bifunctional axon guidance cue and a regulator of vascular and neuronal patterning during development [#1, #3]. As an inhibitory ensheathing cue, Sema5A is expressed by neuroepithelial cells and oligodendrocytes flanking developing axon tracts, where it triggers growth cone collapse and restrains axon elongation to maintain pathway integrity, and contributes to the inhibitory glial environment that limits CNS axon regeneration [#1, #2]. Its short cytoplasmic C-terminal ESSV motif binds the single PDZ domain of SEMCAP-1/GIPC, which redistributes the protein into detergent-resistant surface aggregates and thereby controls its subcellular distribution [#0]. Genetic ablation in mice is embryonic lethal at E11.5–E12.5 with defective remodeling of cranial vasculature, establishing an essential role in vascular patterning [#3], and its thrombospondin (TSP1) repeat domain is required for pro-angiogenic, pro-inflammatory activity driving pannus formation in rheumatoid arthritis [#4]. SEMA5A also acts non-cell-autonomously in cancer: M2 macrophage-derived SEMA5A engages tumor-cell PLXNB3 to enhance aerobic glycolysis and promote pancreatic adenocarcinoma liver metastasis [#6]. Autism-spectrum-disorder-associated gain-of-function variants (R676C, S951C) drive excessive neuronal process elongation through autocrine Plexin-B3 signaling that converges on Rho-family GTPase activation via JNK/RhoG-Elmo1, ErbB2-Dock7-Rac1/Cdc42, and Arf6/FE65/ELMO2-Rac1 cascades [#5, #7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established how the cytoplasmic tail of SEMA5A is read out intracellularly, identifying a PDZ-domain adaptor that controls receptor surface organization.\",\n      \"evidence\": \"Yeast two-hybrid, HEK293 co-expression with detergent-resistance/fluorescence assay, and PDZ/C-terminal mutagenesis\",\n      \"pmids\": [\"10318831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of GIPC-mediated clustering for in vivo signaling not tested\", \"No link to a specific receptor or downstream pathway established here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined SEMA5A as an inhibitory ensheathing guidance cue, showing it produces an invariant repulsive growth cone response that confines retinal axons to their pathway in vivo.\",\n      \"evidence\": \"In situ/IHC localization, growth cone collapse and outgrowth assays, and function-blocking antibody perturbation in ex vivo embryo preparations\",\n      \"pmids\": [\"12506007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating the inhibitory response not identified\", \"Bifunctional context-dependence (attractive vs repulsive) not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended the inhibitory role to glia, showing oligodendrocyte-derived SEMA5A contributes to the non-permissive environment limiting CNS axon regeneration.\",\n      \"evidence\": \"Glial RNA analysis, substrate-bound collapse and outgrowth assays with RGCs, and neutralizing antibody on optic nerve explants\",\n      \"pmids\": [\"15163691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor and intracellular signaling in RGCs not identified\", \"Relevance to in vivo regeneration after injury not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated an essential, non-neuronal developmental requirement by showing SEMA5A loss causes embryonic lethality with defective cranial vascular remodeling.\",\n      \"evidence\": \"Targeted knockout in mice with embryo morphology and cranial vein branching analysis\",\n      \"pmids\": [\"15743826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor and effector pathway in vascular cells not defined\", \"Whether vascular and axonal roles use shared signaling unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed Sema5a as a downstream target of an RNA-binding regulator, linking its dose to synaptic plasticity and cognition.\",\n      \"evidence\": \"FUS transgenic mouse transcriptomics, RNA immunoprecipitation, hippocampal LTP and spine density measurement\",\n      \"pmids\": [\"31509188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct causal contribution of reduced Sema5a to the cognitive phenotype not isolated\", \"Mechanism linking surface SEMA5A to spine density not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the TSP1 domain as the functionally essential module for SEMA5A pro-angiogenic and pro-inflammatory activity in arthritis pathogenesis.\",\n      \"evidence\": \"FLS transcriptomics, proliferation and angiogenesis assays, anti-SEMA5A mAb in CIA mice, and TSP1-deletion rescue in Sema5a-/- CIA mice\",\n      \"pmids\": [\"33616619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor engaged by the TSP1 domain in synoviocytes/endothelium not defined\", \"Downstream angiogenic signaling pathway not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a non-cell-autonomous oncogenic axis in which macrophage-derived SEMA5A signals through tumor PLXNB3 to reprogram metabolism in metastasis.\",\n      \"evidence\": \"PDAC patient samples, intrasplenic injection and KPC mouse models, receptor-ligand studies, and glycolysis assays\",\n      \"pmids\": [\"36741230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between PLXNB3 engagement and glycolytic enzymes not detailed\", \"Reciprocal/structural validation of the SEMA5A-PLXNB3 interaction limited\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed ASD-associated SEMA5A gain-of-function variants drive aberrant neurite elongation via autocrine Plexin-B3 signaling converging on JNK through RhoG-Elmo1.\",\n      \"evidence\": \"Mutant Sema5A expression in N1E-115 cells, confocal localization, JNK activity assay, Plexin-B3 blocking antibody, JNK inhibitor, and Elmo1 RhoG-binding domain construct\",\n      \"pmids\": [\"38133141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which point mutations create gain-of-function not resolved\", \"Confined to cell-line model; in vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved a second effector branch for the R676C variant, identifying the ErbB2-Dock7 axis as a driver of Rac1/Cdc42 overactivation underlying excessive elongation.\",\n      \"evidence\": \"shRNA knockdown of Dock7, ErbB2 kinase inhibition, and Rac1/Cdc42 activity assays in primary cortical neurons and N1E-115 cells\",\n      \"pmids\": [\"41226692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How SEMA5A/Plexin-B3 engages ErbB2 mechanistically not defined\", \"Relationship between this branch and the JNK/RhoG branch not integrated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a third converging branch in which R676C signals through an Arf6/FE65/ELMO2 signalosome to elevate Rac1, with FE65 as the specific coupler.\",\n      \"evidence\": \"CRISPR/Cas13 knockdown of Arf6 and FE65, ELMO2-binding domain rescue, and Rac1 activity assay in primary cortical neurons and N1E-115 cells\",\n      \"pmids\": [\"41703006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How multiple parallel cascades (JNK, ErbB2-Dock7, Arf6-FE65) are coordinated unknown\", \"In vivo confirmation in ASD models lacking\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SEMA5A's shared structural elements (TSP1 domain, ESSV/GIPC tail) and receptor (Plexin-B3) are deployed across its distinct roles in axon guidance, vascular patterning, angiogenic inflammation, and tumor metabolism remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying receptor/effector framework connecting developmental, inflammatory, and oncogenic contexts\", \"Structural basis for ligand-receptor engagement uncharacterized in the corpus\", \"Mechanism distinguishing inhibitory (guidance) from elongation-promoting (mutant) outputs unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 7, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 7, 8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GIPC1\", \"PLXNB3\", \"DOCK7\", \"ERBB2\", \"ARF6\", \"APBB1\", \"ELMO2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}