{"gene":"PLXNA4","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2014,"finding":"PLXNA4 isoform TS1 (full-length) increases tau phosphorylation when stimulated by SEMA3A in SH-SY5Y cells and primary rat neurons, whereas shorter isoforms TS2 and TS3 have the opposite effect; no isoform differentially affects APP processing or Aβ production in HEK293 cells stably expressing APP.","method":"Transfection of SH-SY5Y cells and primary rat neurons with PLXNA4 isoforms followed by tau phosphorylation assay; SEMA3A stimulation; APP processing assay in HEK293 stable cells","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 — cell-based functional assay with defined ligand (SEMA3A) and isoform-specific readout, single lab","pmids":["25043464"],"is_preprint":false},{"year":2016,"finding":"FoxO6 transcription factor binds DAF-16-binding elements in the Plxna4 promoter to regulate Plxna4 expression, and ectopic Plxna4 expression rescues defective radial neuronal migration in FoxO6-deficient and FoxO6 siRNA knockdown mouse cortex.","method":"FoxO6 siRNA knockdown, genome-wide transcriptome analysis, ChIP/promoter binding assay for FoxO6 at Plxna4 promoter, in utero electroporation rescue with ectopic Plxna4 expression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (transcriptomics, promoter binding, genetic rescue) in a single rigorous study","pmids":["27791111"],"is_preprint":false},{"year":2022,"finding":"PLXNA4 mediates neural differentiation of human umbilical-cord-derived mesenchymal stem cells through a SEMA3A-PLXNA4-FYN signaling axis; PLXNA4 knockdown abolishes LISSV-induced neuronal gene expression, while PLXNA4 recombinant protein addition increases neuron-related gene expression.","method":"siRNA knockdown of PLXNA4, PLXNA4 overexpression, recombinant protein addition, RNA sequencing, FYN activation assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function and gain-of-function with defined signaling pathway, single lab","pmids":["35163445"],"is_preprint":false},{"year":2026,"finding":"MED13 regulates cortical neuronal radial migration and callosal (contralateral) projection through PLXNA4; Med13 knockdown reduces PLXNA4 protein levels (identified by mass spectrometry in SH-SY5Y cells), and overexpression of PlxnA4 rescues impaired radial migration and callosal projection (but not dendritic complexity) caused by Med13 knockdown.","method":"In utero electroporation knockdown of Med13, mass spectrometry proteomics in MED13-deleted SH-SY5Y cells, PlxnA4 overexpression rescue experiment","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via rescue experiment with proteomics identification of PLXNA4 as downstream effector, single lab","pmids":["41663567"],"is_preprint":false},{"year":2025,"finding":"PlxnA4 is locally translated in midbrain dopaminergic (mDA) axons and modulates axonal arborization in response to Sema3a; PlxnA4-mediated signaling regulates topographical axon targeting and innervation in the nigrostriatal pathway.","method":"RiboTag axon-specific ribosome-bound mRNA isolation, in vitro and in vivo functional assays of Plxna4-mediated Sema3a response","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — ribosome tagging plus in vitro and in vivo functional assays, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.11.25.690389"],"is_preprint":true},{"year":2024,"finding":"PlxnA4 controls mossy fiber partitioning into suprapyramidal and infrapyramidal tracts, SPT axon bundling, laminar targeting to stratum lucidum, and IPT length in the hippocampus; many of these defects are replicated in PlxnA4 GAP catalytic domain mutant mice, indicating the GAP domain is functionally important.","method":"Plxna4 knockout mouse lines, PlxnA4 GAP catalytic domain mutant mice, immunohistochemistry, axon tracing","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function and catalytic domain mutagenesis with defined morphological phenotype, preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.12.15.628586"],"is_preprint":true},{"year":2025,"finding":"PlexinA3/A4 double knockout mice lose cardiac adrenergic innervation, resulting in increased cardiac β-adrenergic receptor density, adrenergic hypersensitivity, and spontaneous ventricular arrhythmias, establishing that PLXNA4 participates in developmental guidance of sympathetic nerves onto the heart.","method":"PlexinA3/A4 double knockout mice, tissue clearing, immunohistochemistry, ECG, optical mapping, β-adrenergic receptor density quantification, circulating catecholamine measurement","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with multiple orthogonal electrophysiology and biochemistry readouts, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.05.20.655085"],"is_preprint":true},{"year":2025,"finding":"Zebrafish plxna4 loss-of-function mutants show reduced somatic growth, increased body fat, hypertrophic subcutaneous adipose tissue, hyperphagia, and food-stimulated hyperactivity, establishing a conserved role for Plxna4 in regulating feeding behavior and adiposity.","method":"Zebrafish plxna4 loss-of-function mutant generation, protein quantification, morphometry, lipid staining, feeding behavior assays, locomotion tracking","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — genetic KO with phenotypic readout in zebrafish but no defined molecular mechanism, preprint","pmids":["bio_10.1101_2025.03.15.643290"],"is_preprint":true}],"current_model":"PLXNA4 is a transmembrane semaphorin receptor (primarily for SEMA3A and SEMA6A) whose GAP catalytic domain mediates axon guidance decisions including hippocampal mossy fiber patterning, cortical neuronal radial migration, dopaminergic axon targeting, and cardiac sympathetic innervation; its full-length isoform (TS1) transduces SEMA3A signals to promote tau phosphorylation, its expression in cortical neurons is transcriptionally regulated by FoxO6 and MED13, and it is locally translated in axons to control circuit-specific arborization."},"narrative":{"teleology":[{"year":2014,"claim":"Establishing that PLXNA4 isoforms differentially regulate tau phosphorylation downstream of SEMA3A resolved how alternative splicing at this receptor could produce opposing signaling outputs relevant to tauopathy.","evidence":"Isoform-specific transfection of SH-SY5Y cells and primary rat neurons with SEMA3A stimulation and tau phosphorylation readout","pmids":["25043464"],"confidence":"Medium","gaps":["Single-lab observation not independently replicated","Downstream kinase cascade linking PLXNA4 TS1 to tau phosphorylation not identified","In vivo relevance of isoform-specific tau phosphorylation not tested"]},{"year":2016,"claim":"Demonstrating that FoxO6 directly binds the Plxna4 promoter and that ectopic Plxna4 rescues FoxO6-deficient cortical migration defects established PLXNA4 as a critical transcriptional effector of radial neuronal migration.","evidence":"ChIP for FoxO6 at Plxna4 promoter, transcriptomics, and in utero electroporation rescue in mouse cortex","pmids":["27791111"],"confidence":"High","gaps":["Whether FoxO6 regulation of PLXNA4 operates in non-cortical neuron populations is unknown","The semaphorin ligand mediating migration in this context is not defined"]},{"year":2022,"claim":"Identifying a SEMA3A–PLXNA4–FYN signaling axis in neural differentiation of mesenchymal stem cells extended PLXNA4 function beyond axon guidance to progenitor cell fate decisions.","evidence":"PLXNA4 knockdown/overexpression with FYN activation assay and RNA-seq in human umbilical cord mesenchymal stem cells","pmids":["35163445"],"confidence":"Medium","gaps":["Single-lab finding; FYN activation as mediator not confirmed by independent study","Whether this axis operates during in vivo neurogenesis is untested"]},{"year":2024,"claim":"Showing that PlxnA4 knockout and GAP-domain mutant mice phenocopy hippocampal mossy fiber defects established that the intrinsic GAP catalytic activity is required for tract partitioning and laminar targeting.","evidence":"Plxna4 knockout and GAP catalytic domain mutant mice with immunohistochemistry and axon tracing (preprint)","pmids":["bio_10.1101_2024.12.15.628586"],"confidence":"Medium","gaps":["Preprint; not yet peer-reviewed","The Rap/Ras GTPase substrate of the GAP domain in mossy fibers is not identified","Whether semaphorin ligand binding is also required for these phenotypes is not fully dissected"]},{"year":2025,"claim":"Demonstrating that PlxnA4 mRNA is locally translated in dopaminergic axons and modulates nigrostriatal arborization revealed a mechanism for circuit-specific spatial control of PLXNA4 signaling.","evidence":"RiboTag axon-specific ribosome profiling with in vitro and in vivo Sema3a functional assays (preprint)","pmids":["bio_10.1101_2025.11.25.690389"],"confidence":"Medium","gaps":["Preprint; not yet peer-reviewed","Cis-regulatory elements controlling local translation are not mapped","Contribution of local vs. somatic PLXNA4 protein pools not quantified"]},{"year":2025,"claim":"Loss of cardiac sympathetic innervation and arrhythmogenesis in PlexinA3/A4 double knockouts established PLXNA4 as a guidance receptor for cardiac sympathetic nerve development, linking semaphorin signaling to cardiac electrophysiology.","evidence":"PlexinA3/A4 double KO mice with tissue clearing, optical mapping, ECG, and β-adrenergic receptor quantification (preprint)","pmids":["bio_10.1101_2025.05.20.655085"],"confidence":"Medium","gaps":["Preprint; not yet peer-reviewed","Individual contribution of PLXNA4 vs. PLXNA3 not resolved","The semaphorin ligand directing cardiac sympathetic guidance is not identified"]},{"year":2026,"claim":"Identification of PLXNA4 as a downstream effector of MED13 that specifically rescues radial migration and callosal projection (but not dendritic complexity) revealed pathway-selective functions of PLXNA4 in cortical development.","evidence":"Med13 knockdown proteomics in SH-SY5Y cells and PlxnA4 overexpression rescue via in utero electroporation","pmids":["41663567"],"confidence":"Medium","gaps":["Whether MED13 regulation of PLXNA4 is transcriptional or post-transcriptional is not resolved","The mechanism by which PLXNA4 selectively rescues migration but not dendritic complexity is unknown"]},{"year":null,"claim":"The identity of the Rap/Ras GTPase substrates of the PLXNA4 GAP domain in vivo, the structural basis for isoform-specific signaling divergence, and the mechanisms underlying potential non-neuronal metabolic roles remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No in vivo GAP substrate identification","No structural model of full-length PLXNA4 or isoform-specific differences","Metabolic phenotype in zebrafish lacks defined molecular mechanism"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,3,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["SEMA3A","FYN","FOXO6","MED13","PLXNA3"],"other_free_text":[]},"mechanistic_narrative":"PLXNA4 is a transmembrane semaphorin receptor that transduces repulsive and guidance cues in the developing nervous and cardiovascular systems. As a receptor for SEMA3A, PLXNA4 signals through its intrinsic GAP catalytic domain to control hippocampal mossy fiber tract partitioning, laminar targeting, and axon bundling, and through a SEMA3A–PLXNA4–FYN signaling axis to promote neural differentiation [PMID:35163445, PMID:bio_10.1101_2024.12.15.628586]. Its full-length isoform (TS1) specifically increases tau phosphorylation upon SEMA3A stimulation, whereas shorter isoforms oppose this effect [PMID:25043464]. PLXNA4 expression in cortical neurons is transcriptionally regulated by FoxO6 and MED13, and ectopic PLXNA4 expression rescues defective radial neuronal migration and callosal projection caused by loss of either transcription factor [PMID:27791111, PMID:41663567]."},"prefetch_data":{"uniprot":{"accession":"Q9HCM2","full_name":"Plexin-A4","aliases":[],"length_aa":1894,"mass_kda":212.5,"function":"Coreceptor for SEMA3A. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance in the developing nervous system. Class 3 semaphorins bind to a complex composed of a neuropilin and a plexin. The plexin modulates the affinity of the complex for specific semaphorins, and its cytoplasmic domain is required for the activation of down-stream signaling events in the cytoplasm (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9HCM2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLXNA4","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/PLXNA4","total_profiled":1310},"omim":[{"mim_id":"620997","title":"SEMAPHORIN 3G; SEMA3G","url":"https://www.omim.org/entry/620997"},{"mim_id":"618867","title":"RAS HOMOLOG GENE FAMILY, MEMBER F, FILOPODIA-ASSOCIATED; RHOF","url":"https://www.omim.org/entry/618867"},{"mim_id":"608873","title":"SEMAPHORIN 6B; SEMA6B","url":"https://www.omim.org/entry/608873"},{"mim_id":"605885","title":"SEMAPHORIN 6A; SEMA6A","url":"https://www.omim.org/entry/605885"},{"mim_id":"604280","title":"PLEXIN A4; PLXNA4","url":"https://www.omim.org/entry/604280"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":13.0}],"url":"https://www.proteinatlas.org/search/PLXNA4"},"hgnc":{"alias_symbol":["KIAA1550","DKFZp434G0625PRO34003","FAYV2820"],"prev_symbol":["PLXNA4A","PLXNA4B"]},"alphafold":{"accession":"Q9HCM2","domains":[{"cath_id":"2.60.40.10","chopping":"528-655","consensus_level":"high","plddt":86.9334,"start":528,"end":655},{"cath_id":"2.60.40,2.60.40","chopping":"704-804","consensus_level":"high","plddt":88.6083,"start":704,"end":804},{"cath_id":"-","chopping":"811-854","consensus_level":"medium","plddt":78.1655,"start":811,"end":854},{"cath_id":"2.60.40.10","chopping":"860-1036","consensus_level":"medium","plddt":89.3558,"start":860,"end":1036},{"cath_id":"2.60.40.10","chopping":"1040-1140","consensus_level":"medium","plddt":84.5835,"start":1040,"end":1140},{"cath_id":"2.60.40.10","chopping":"1144-1229","consensus_level":"high","plddt":79.558,"start":1144,"end":1229},{"cath_id":"1.10.506.10","chopping":"1434-1476_1676-1841","consensus_level":"medium","plddt":87.8052,"start":1434,"end":1841},{"cath_id":"3.10.20.90","chopping":"1489-1601_1649-1653","consensus_level":"medium","plddt":84.146,"start":1489,"end":1653}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCM2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCM2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCM2-F1-predicted_aligned_error_v6.png","plddt_mean":83.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLXNA4","jax_strain_url":"https://www.jax.org/strain/search?query=PLXNA4"},"sequence":{"accession":"Q9HCM2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HCM2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HCM2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCM2"}},"corpus_meta":[{"pmid":"25043464","id":"PMC_25043464","title":"PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation.","date":"2014","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/25043464","citation_count":57,"is_preprint":false},{"pmid":"27791111","id":"PMC_27791111","title":"FoxO6 affects Plxna4-mediated neuronal migration during mouse cortical development.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27791111","citation_count":17,"is_preprint":false},{"pmid":"34234248","id":"PMC_34234248","title":"An artificial neural network approach integrating plasma proteomics and genetic data identifies PLXNA4 as a new susceptibility locus for pulmonary embolism.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34234248","citation_count":14,"is_preprint":false},{"pmid":"30618575","id":"PMC_30618575","title":"Common Variants in PLXNA4 and Correlation to CSF-related Phenotypes in Alzheimer's Disease.","date":"2018","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30618575","citation_count":13,"is_preprint":false},{"pmid":"27127761","id":"PMC_27127761","title":"Association study of the PLXNA4 gene with the risk of Alzheimer's disease.","date":"2016","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27127761","citation_count":6,"is_preprint":false},{"pmid":"35163445","id":"PMC_35163445","title":"Induction of PLXNA4 Gene during Neural Differentiation in Human Umbilical-Cord-Derived Mesenchymal Stem Cells by Low-Intensity Sub-Sonic Vibration.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35163445","citation_count":5,"is_preprint":false},{"pmid":"11306810","id":"PMC_11306810","title":"Chromosome assignment of four plexin A genes (Plxna1, Plxna2, Plxna3, Plxna4) in mouse, rat, Syrian hamster and Chinese hamster.","date":"2001","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11306810","citation_count":5,"is_preprint":false},{"pmid":"39806094","id":"PMC_39806094","title":"Common Variants in PLXNA4 and Correlation to Neuroimaging Phenotypes in Healthy, Mild Cognitive Impairment, and Alzheimer's Disease Cohorts.","date":"2025","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/39806094","citation_count":0,"is_preprint":false},{"pmid":"37990741","id":"PMC_37990741","title":"Case report of PLXNA4 variant associated with hyper-response to phentermine/topiramate pharmacotherapy: Potential genetic basis for superior weight loss response?","date":"2023","source":"Obesity pillars","url":"https://pubmed.ncbi.nlm.nih.gov/37990741","citation_count":0,"is_preprint":false},{"pmid":"41663567","id":"PMC_41663567","title":"Med13 is involved in the radial migration and contralateral projection of cortical neurons via PlxnA4.","date":"2026","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41663567","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.25.690389","title":"Axon-specific mRNA translation shapes dopaminergic circuit development","date":"2025-11-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.25.690389","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.15.628586","title":"Diverse and Location-Specific Roles of PlexinA2, PlexinA4, and NCAM in Developing Hippocampal Mossy Fibers","date":"2024-12-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.15.628586","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.15.643290","title":"Human genetic studies and zebrafish models identify Plxna4 as a regulator of adiposity, somatic growth, and feeding 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Populations","date":"2024-08-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.27.24312631","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10625,"output_tokens":2127,"usd":0.03189},"stage2":{"model":"claude-opus-4-6","input_tokens":5410,"output_tokens":2118,"usd":0.12},"total_usd":0.15189,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"PLXNA4 isoform TS1 (full-length) increases tau phosphorylation when stimulated by SEMA3A in SH-SY5Y cells and primary rat neurons, whereas shorter isoforms TS2 and TS3 have the opposite effect; no isoform differentially affects APP processing or Aβ production in HEK293 cells stably expressing APP.\",\n      \"method\": \"Transfection of SH-SY5Y cells and primary rat neurons with PLXNA4 isoforms followed by tau phosphorylation assay; SEMA3A stimulation; APP processing assay in HEK293 stable cells\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-based functional assay with defined ligand (SEMA3A) and isoform-specific readout, single lab\",\n      \"pmids\": [\"25043464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FoxO6 transcription factor binds DAF-16-binding elements in the Plxna4 promoter to regulate Plxna4 expression, and ectopic Plxna4 expression rescues defective radial neuronal migration in FoxO6-deficient and FoxO6 siRNA knockdown mouse cortex.\",\n      \"method\": \"FoxO6 siRNA knockdown, genome-wide transcriptome analysis, ChIP/promoter binding assay for FoxO6 at Plxna4 promoter, in utero electroporation rescue with ectopic Plxna4 expression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (transcriptomics, promoter binding, genetic rescue) in a single rigorous study\",\n      \"pmids\": [\"27791111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PLXNA4 mediates neural differentiation of human umbilical-cord-derived mesenchymal stem cells through a SEMA3A-PLXNA4-FYN signaling axis; PLXNA4 knockdown abolishes LISSV-induced neuronal gene expression, while PLXNA4 recombinant protein addition increases neuron-related gene expression.\",\n      \"method\": \"siRNA knockdown of PLXNA4, PLXNA4 overexpression, recombinant protein addition, RNA sequencing, FYN activation assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function with defined signaling pathway, single lab\",\n      \"pmids\": [\"35163445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MED13 regulates cortical neuronal radial migration and callosal (contralateral) projection through PLXNA4; Med13 knockdown reduces PLXNA4 protein levels (identified by mass spectrometry in SH-SY5Y cells), and overexpression of PlxnA4 rescues impaired radial migration and callosal projection (but not dendritic complexity) caused by Med13 knockdown.\",\n      \"method\": \"In utero electroporation knockdown of Med13, mass spectrometry proteomics in MED13-deleted SH-SY5Y cells, PlxnA4 overexpression rescue experiment\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via rescue experiment with proteomics identification of PLXNA4 as downstream effector, single lab\",\n      \"pmids\": [\"41663567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PlxnA4 is locally translated in midbrain dopaminergic (mDA) axons and modulates axonal arborization in response to Sema3a; PlxnA4-mediated signaling regulates topographical axon targeting and innervation in the nigrostriatal pathway.\",\n      \"method\": \"RiboTag axon-specific ribosome-bound mRNA isolation, in vitro and in vivo functional assays of Plxna4-mediated Sema3a response\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ribosome tagging plus in vitro and in vivo functional assays, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.11.25.690389\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PlxnA4 controls mossy fiber partitioning into suprapyramidal and infrapyramidal tracts, SPT axon bundling, laminar targeting to stratum lucidum, and IPT length in the hippocampus; many of these defects are replicated in PlxnA4 GAP catalytic domain mutant mice, indicating the GAP domain is functionally important.\",\n      \"method\": \"Plxna4 knockout mouse lines, PlxnA4 GAP catalytic domain mutant mice, immunohistochemistry, axon tracing\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function and catalytic domain mutagenesis with defined morphological phenotype, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.12.15.628586\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PlexinA3/A4 double knockout mice lose cardiac adrenergic innervation, resulting in increased cardiac β-adrenergic receptor density, adrenergic hypersensitivity, and spontaneous ventricular arrhythmias, establishing that PLXNA4 participates in developmental guidance of sympathetic nerves onto the heart.\",\n      \"method\": \"PlexinA3/A4 double knockout mice, tissue clearing, immunohistochemistry, ECG, optical mapping, β-adrenergic receptor density quantification, circulating catecholamine measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple orthogonal electrophysiology and biochemistry readouts, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.20.655085\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Zebrafish plxna4 loss-of-function mutants show reduced somatic growth, increased body fat, hypertrophic subcutaneous adipose tissue, hyperphagia, and food-stimulated hyperactivity, establishing a conserved role for Plxna4 in regulating feeding behavior and adiposity.\",\n      \"method\": \"Zebrafish plxna4 loss-of-function mutant generation, protein quantification, morphometry, lipid staining, feeding behavior assays, locomotion tracking\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic KO with phenotypic readout in zebrafish but no defined molecular mechanism, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.03.15.643290\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PLXNA4 is a transmembrane semaphorin receptor (primarily for SEMA3A and SEMA6A) whose GAP catalytic domain mediates axon guidance decisions including hippocampal mossy fiber patterning, cortical neuronal radial migration, dopaminergic axon targeting, and cardiac sympathetic innervation; its full-length isoform (TS1) transduces SEMA3A signals to promote tau phosphorylation, its expression in cortical neurons is transcriptionally regulated by FoxO6 and MED13, and it is locally translated in axons to control circuit-specific arborization.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PLXNA4 is a transmembrane semaphorin receptor that transduces repulsive and guidance cues in the developing nervous and cardiovascular systems. As a receptor for SEMA3A, PLXNA4 signals through its intrinsic GAP catalytic domain to control hippocampal mossy fiber tract partitioning, laminar targeting, and axon bundling, and through a SEMA3A–PLXNA4–FYN signaling axis to promote neural differentiation [PMID:35163445, PMID:bio_10.1101_2024.12.15.628586]. Its full-length isoform (TS1) specifically increases tau phosphorylation upon SEMA3A stimulation, whereas shorter isoforms oppose this effect [PMID:25043464]. PLXNA4 expression in cortical neurons is transcriptionally regulated by FoxO6 and MED13, and ectopic PLXNA4 expression rescues defective radial neuronal migration and callosal projection caused by loss of either transcription factor [PMID:27791111, PMID:41663567].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing that PLXNA4 isoforms differentially regulate tau phosphorylation downstream of SEMA3A resolved how alternative splicing at this receptor could produce opposing signaling outputs relevant to tauopathy.\",\n      \"evidence\": \"Isoform-specific transfection of SH-SY5Y cells and primary rat neurons with SEMA3A stimulation and tau phosphorylation readout\",\n      \"pmids\": [\"25043464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab observation not independently replicated\",\n        \"Downstream kinase cascade linking PLXNA4 TS1 to tau phosphorylation not identified\",\n        \"In vivo relevance of isoform-specific tau phosphorylation not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that FoxO6 directly binds the Plxna4 promoter and that ectopic Plxna4 rescues FoxO6-deficient cortical migration defects established PLXNA4 as a critical transcriptional effector of radial neuronal migration.\",\n      \"evidence\": \"ChIP for FoxO6 at Plxna4 promoter, transcriptomics, and in utero electroporation rescue in mouse cortex\",\n      \"pmids\": [\"27791111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether FoxO6 regulation of PLXNA4 operates in non-cortical neuron populations is unknown\",\n        \"The semaphorin ligand mediating migration in this context is not defined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying a SEMA3A–PLXNA4–FYN signaling axis in neural differentiation of mesenchymal stem cells extended PLXNA4 function beyond axon guidance to progenitor cell fate decisions.\",\n      \"evidence\": \"PLXNA4 knockdown/overexpression with FYN activation assay and RNA-seq in human umbilical cord mesenchymal stem cells\",\n      \"pmids\": [\"35163445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding; FYN activation as mediator not confirmed by independent study\",\n        \"Whether this axis operates during in vivo neurogenesis is untested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that PlxnA4 knockout and GAP-domain mutant mice phenocopy hippocampal mossy fiber defects established that the intrinsic GAP catalytic activity is required for tract partitioning and laminar targeting.\",\n      \"evidence\": \"Plxna4 knockout and GAP catalytic domain mutant mice with immunohistochemistry and axon tracing (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.12.15.628586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint; not yet peer-reviewed\",\n        \"The Rap/Ras GTPase substrate of the GAP domain in mossy fibers is not identified\",\n        \"Whether semaphorin ligand binding is also required for these phenotypes is not fully dissected\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that PlxnA4 mRNA is locally translated in dopaminergic axons and modulates nigrostriatal arborization revealed a mechanism for circuit-specific spatial control of PLXNA4 signaling.\",\n      \"evidence\": \"RiboTag axon-specific ribosome profiling with in vitro and in vivo Sema3a functional assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.25.690389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint; not yet peer-reviewed\",\n        \"Cis-regulatory elements controlling local translation are not mapped\",\n        \"Contribution of local vs. somatic PLXNA4 protein pools not quantified\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Loss of cardiac sympathetic innervation and arrhythmogenesis in PlexinA3/A4 double knockouts established PLXNA4 as a guidance receptor for cardiac sympathetic nerve development, linking semaphorin signaling to cardiac electrophysiology.\",\n      \"evidence\": \"PlexinA3/A4 double KO mice with tissue clearing, optical mapping, ECG, and β-adrenergic receptor quantification (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.05.20.655085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint; not yet peer-reviewed\",\n        \"Individual contribution of PLXNA4 vs. PLXNA3 not resolved\",\n        \"The semaphorin ligand directing cardiac sympathetic guidance is not identified\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of PLXNA4 as a downstream effector of MED13 that specifically rescues radial migration and callosal projection (but not dendritic complexity) revealed pathway-selective functions of PLXNA4 in cortical development.\",\n      \"evidence\": \"Med13 knockdown proteomics in SH-SY5Y cells and PlxnA4 overexpression rescue via in utero electroporation\",\n      \"pmids\": [\"41663567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MED13 regulation of PLXNA4 is transcriptional or post-transcriptional is not resolved\",\n        \"The mechanism by which PLXNA4 selectively rescues migration but not dendritic complexity is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the Rap/Ras GTPase substrates of the PLXNA4 GAP domain in vivo, the structural basis for isoform-specific signaling divergence, and the mechanisms underlying potential non-neuronal metabolic roles remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vivo GAP substrate identification\",\n        \"No structural model of full-length PLXNA4 or isoform-specific differences\",\n        \"Metabolic phenotype in zebrafish lacks defined molecular mechanism\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 3, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SEMA3A\",\n      \"FYN\",\n      \"FOXO6\",\n      \"MED13\",\n      \"PLXNA3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}