{"gene":"PLXNA2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2013,"finding":"TMPRSS2:ERG fusion directly and positively regulates PLXNA2 expression in prostate cancer cells (PC3c), and PLXNA2 upregulation contributes to TMPRSS2:ERG-mediated enhancement of cell migration and invasion in a dose-dependent manner. PLXNA2 expression is also elevated in metastatic PCa tumors compared with localized primary PCa tumors.","method":"Microarray analysis, ectopic expression of TMPRSS2:ERG at multiple doses, migration/invasion assays with PLXNA2 manipulation, immunohistochemistry of clinical samples","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown/overexpression with defined phenotypic readout (migration/invasion), and correlation with clinical cohort; single lab, multiple orthogonal methods but no biochemical mechanism for how PLXNA2 drives invasion","pmids":["23708657"],"is_preprint":false},{"year":2021,"finding":"PLXNA2 knockdown in rats with middle cerebral artery occlusion/reperfusion injury promotes microglial polarization from M1 (pro-inflammatory) to M2 (anti-inflammatory) phenotype, reduces neuroinflammation, and accelerates recovery of motor and cognitive function. The mTOR/STAT3 signaling pathway is mechanistically involved in PLXNA2-regulated microglia polarization.","method":"PLXNA2 knockdown in MCAO/R rat model and BV2 microglia with OGD/R; behavioral tests, immunofluorescence, qRT-PCR, Western blot for M1/M2 markers and mTOR/STAT3 pathway components","journal":"Experimental Neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (microglia polarization) and pathway identification (mTOR/STAT3), single lab, multiple orthogonal readouts","pmids":["34474008"],"is_preprint":false},{"year":2014,"finding":"In zebrafish, Plxna2 acts together with Sema6a (semaphorin 6a) to maintain eye vesicle cohesion during morphogenesis. sema6a is expressed throughout the eye vesicle while plxna2 is restricted to the ventral vesicle; knockdown of either causes loss of vesicle integrity with eye progenitors failing to enter evaginating vesicles or delaminating from the eye epithelium. Simultaneous knockdown of both sema6a and plxna2 rescues eye vesicle integrity, indicating that neutralization of Sema6a/Plxna2-mediated repulsion promotes cell-cell interactions within the tissue domain.","method":"Morpholino knockdown of plxna2 and/or sema6a in zebrafish; time-lapse microscopy; explant experiments; epistasis rescue by double knockdown","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (double knockdown rescue), time-lapse live imaging, explant experiments, multiple orthogonal methods establishing tissue-autonomous mechanism in a model organism","pmids":["24917502"],"is_preprint":false}],"current_model":"PLXNA2 (Plexin A2) is a transmembrane semaphorin receptor that mediates repulsive cell-guidance signaling: in zebrafish, Plxna2 acts with Sema6a to regulate spatially restricted repulsion that maintains eye vesicle cohesion during morphogenesis; in mammalian contexts, PLXNA2 promotes prostate cancer cell migration and invasion downstream of the TMPRSS2:ERG oncogenic fusion, and regulates microglial polarization (M1-to-M2 switch) after ischemia/reperfusion injury via mTOR/STAT3 signaling."},"narrative":{"mechanistic_narrative":"PLXNA2 (Plexin A2) is a semaphorin co-receptor that transduces cell-guidance signals governing tissue morphogenesis, cell migration, and inflammatory cell states [PMID:24917502]. During zebrafish eye morphogenesis, Plxna2 partners with the semaphorin Sema6a to mediate spatially restricted repulsion: sema6a is expressed throughout the eye vesicle while plxna2 is confined to the ventral vesicle, and genetic epistasis shows that simultaneous removal of both restores vesicle integrity, establishing that Sema6a/Plxna2 repulsion must be locally neutralized to permit cohesive cell-cell interactions within the tissue domain [PMID:24917502]. In mammalian disease contexts, PLXNA2 is a direct transcriptional target of the TMPRSS2:ERG oncogenic fusion and acts dose-dependently downstream of it to drive prostate cancer cell migration and invasion, with elevated expression in metastatic relative to localized tumors [PMID:23708657]. PLXNA2 also regulates microglial polarization after cerebral ischemia/reperfusion injury, where its loss shifts microglia from a pro-inflammatory M1 to an anti-inflammatory M2 state through mTOR/STAT3 signaling [PMID:34474008]. The biochemical mechanism by which PLXNA2 couples semaphorin engagement to these downstream migratory and signaling outputs has not been characterized in the available corpus.","teleology":[{"year":2013,"claim":"Established that PLXNA2 is a downstream effector of an oncogenic transcription factor fusion, linking semaphorin receptor expression to cancer cell invasiveness.","evidence":"Microarray, dose-titrated ectopic TMPRSS2:ERG expression, PLXNA2 knockdown/overexpression with migration/invasion assays, and IHC of clinical prostate cancer samples","pmids":["23708657"],"confidence":"Medium","gaps":["No biochemical mechanism for how PLXNA2 drives migration/invasion","Ligand and signaling partners in prostate cancer not identified","Single lab; causality in metastasis not tested in vivo"]},{"year":2014,"claim":"Defined the core ligand-receptor pairing and showed that spatially restricted Sema6a/Plxna2 repulsion controls tissue cohesion during organ morphogenesis.","evidence":"Morpholino single and double knockdown with epistasis rescue, time-lapse live imaging, and explant experiments in zebrafish","pmids":["24917502"],"confidence":"High","gaps":["Intracellular signaling downstream of Plxna2 not resolved","Established in zebrafish; mammalian morphogenetic role not tested","Structural basis of Sema6a-Plxna2 interaction not addressed"]},{"year":2021,"claim":"Extended PLXNA2 function to neuroinflammation, identifying mTOR/STAT3 as the pathway through which it controls microglial polarization after ischemic injury.","evidence":"PLXNA2 knockdown in MCAO/R rat model and OGD/R BV2 microglia with behavioral tests, immunofluorescence, qRT-PCR, and Western blot of M1/M2 and mTOR/STAT3 markers","pmids":["34474008"],"confidence":"Medium","gaps":["Whether PLXNA2 acts cell-autonomously in microglia versus via an upstream semaphorin is unresolved","Direct molecular link between PLXNA2 and mTOR/STAT3 not established","Single lab; human relevance not tested"]},{"year":null,"claim":"The biochemical signal-transduction mechanism connecting PLXNA2 semaphorin engagement to downstream migratory and inflammatory outputs remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or enzymatic mechanism for PLXNA2 signaling in the corpus","Co-receptors and cytoplasmic effectors across contexts not identified","Unifying model across morphogenesis, cancer, and inflammation absent"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0]}],"complexes":[],"partners":["SEMA6A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75051","full_name":"Plexin-A2","aliases":["Semaphorin receptor OCT"],"length_aa":1894,"mass_kda":211.1,"function":"Coreceptor for SEMA3A and SEMA6A. 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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/O75051/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLXNA2","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLXNA2","total_profiled":1310},"omim":[{"mim_id":"616186","title":"H19/IGF2-IMPRINTING CONTROL REGION","url":"https://www.omim.org/entry/616186"},{"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"},{"mim_id":"601866","title":"SEMAPHORIN 4D; SEMA4D","url":"https://www.omim.org/entry/601866"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in 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protein Oct-6 is a nucleocytoplasmic shuttling protein.","date":"2005","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/16260476","citation_count":22,"is_preprint":false},{"pmid":"27063953","id":"PMC_27063953","title":"Oct-1, to go or not to go? That is the PolII question.","date":"2016","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/27063953","citation_count":21,"is_preprint":false},{"pmid":"37924591","id":"PMC_37924591","title":"Optical coherence tomography (OCT) measurements and disability in multiple sclerosis (MS): A systematic review and meta-analysis.","date":"2023","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37924591","citation_count":21,"is_preprint":false},{"pmid":"36396812","id":"PMC_36396812","title":"Optical coherence tomography (OCT) measurements and cognitive performance in multiple sclerosis: a systematic review and meta-analysis.","date":"2022","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36396812","citation_count":21,"is_preprint":false},{"pmid":"24532469","id":"PMC_24532469","title":"Clinical significance of the stem cell gene Oct-4 in cervical cancer.","date":"2014","source":"Tumour biology : the journal of 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research","url":"https://pubmed.ncbi.nlm.nih.gov/40054600","citation_count":20,"is_preprint":false},{"pmid":"31158044","id":"PMC_31158044","title":"Imaging Amblyopia: Insights from Optical Coherence Tomography (OCT).","date":"2019","source":"Seminars in ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/31158044","citation_count":20,"is_preprint":false},{"pmid":"36276927","id":"PMC_36276927","title":"Virtual Reality Oculokinetic Perimetry Test Reproducibility and Relationship to Conventional Perimetry and OCT.","date":"2021","source":"Ophthalmology science","url":"https://pubmed.ncbi.nlm.nih.gov/36276927","citation_count":20,"is_preprint":false},{"pmid":"12663137","id":"PMC_12663137","title":"Human Oct-1L isoform has tissue-specific expression pattern similar to Oct-2.","date":"2003","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/12663137","citation_count":20,"is_preprint":false},{"pmid":"9651490","id":"PMC_9651490","title":"Comparison of sequence and function of the Oct-6 genes in zebrafish, chicken and mouse.","date":"1998","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/9651490","citation_count":20,"is_preprint":false},{"pmid":"16582106","id":"PMC_16582106","title":"Btk expression is controlled by Oct and BOB.1/OBF.1.","date":"2006","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/16582106","citation_count":19,"is_preprint":false},{"pmid":"32832255","id":"PMC_32832255","title":"Comparison of Rates of Progression of Macular OCT Measures in Glaucoma.","date":"2020","source":"Translational vision science & technology","url":"https://pubmed.ncbi.nlm.nih.gov/32832255","citation_count":19,"is_preprint":false},{"pmid":"27126747","id":"PMC_27126747","title":"Role of OCT-1 and partner proteins in T cell differentiation.","date":"2016","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/27126747","citation_count":18,"is_preprint":false},{"pmid":"17564582","id":"PMC_17564582","title":"The EWS-Oct-4 fusion gene encodes a transforming gene.","date":"2007","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/17564582","citation_count":18,"is_preprint":false},{"pmid":"22381206","id":"PMC_22381206","title":"Spatial and temporal distribution of Oct-4 and acetylated H4K5 in rabbit embryos.","date":"2012","source":"Reproductive biomedicine online","url":"https://pubmed.ncbi.nlm.nih.gov/22381206","citation_count":18,"is_preprint":false},{"pmid":"35650321","id":"PMC_35650321","title":"Ability of Swept-source OCT and OCT-angiography to detect neuroretinal and vasculature changes in patients with Parkinson disease and essential tremor.","date":"2022","source":"Eye (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/35650321","citation_count":18,"is_preprint":false},{"pmid":"12091196","id":"PMC_12091196","title":"Expression of Oct-6, a POU III domain transcription factor, in schizophrenia.","date":"2002","source":"The American journal of psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/12091196","citation_count":18,"is_preprint":false},{"pmid":"37522023","id":"PMC_37522023","title":"OCT and OCT-A biomarkers in multiple sclerosis - review.","date":"2023","source":"Romanian journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/37522023","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46619,"output_tokens":1397,"usd":0.080406,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7623,"output_tokens":1715,"usd":0.040495,"stage2_stop_reason":"end_turn"},"total_usd":0.120901,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through these 100 papers, I need to identify which ones are actually about PLXNA2 (Plexin A2, the semaphorin receptor). The vast majority of papers are about OCT (Optical Coherence Tomography) imaging technology or OCT/Oct transcription factors (POU domain proteins like Oct-1, Oct-2, Oct-4, Oct-6), which are completely different from PLXNA2.\n\nThe relevant PLXNA2 papers are:\n- [21] PMID:16402134 - schizophrenia association (genetic/epidemiological, not mechanistic)\n- [42] PMID:23708657 - TMPRSS2:ERG and PLXNA2 in prostate cancer metastasis\n- [48] PMID:17339520 - anxiety association (genetic, not mechanistic)\n- [56] PMID:34474008 - PLXNA2 knockdown, microglia polarization, mTOR/STAT3\n- [68] PMID:24917502 - Sema6a/Plxna2 in zebrafish eye vesicle cohesion\n- [73] PMID:16932874 - SNP association with osteoporosis (genetic, not mechanistic)\n- [79] PMID:17346868 - failure to replicate schizophrenia association (negative)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"TMPRSS2:ERG fusion directly and positively regulates PLXNA2 expression in prostate cancer cells (PC3c), and PLXNA2 upregulation contributes to TMPRSS2:ERG-mediated enhancement of cell migration and invasion in a dose-dependent manner. PLXNA2 expression is also elevated in metastatic PCa tumors compared with localized primary PCa tumors.\",\n      \"method\": \"Microarray analysis, ectopic expression of TMPRSS2:ERG at multiple doses, migration/invasion assays with PLXNA2 manipulation, immunohistochemistry of clinical samples\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown/overexpression with defined phenotypic readout (migration/invasion), and correlation with clinical cohort; single lab, multiple orthogonal methods but no biochemical mechanism for how PLXNA2 drives invasion\",\n      \"pmids\": [\"23708657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PLXNA2 knockdown in rats with middle cerebral artery occlusion/reperfusion injury promotes microglial polarization from M1 (pro-inflammatory) to M2 (anti-inflammatory) phenotype, reduces neuroinflammation, and accelerates recovery of motor and cognitive function. The mTOR/STAT3 signaling pathway is mechanistically involved in PLXNA2-regulated microglia polarization.\",\n      \"method\": \"PLXNA2 knockdown in MCAO/R rat model and BV2 microglia with OGD/R; behavioral tests, immunofluorescence, qRT-PCR, Western blot for M1/M2 markers and mTOR/STAT3 pathway components\",\n      \"journal\": \"Experimental Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (microglia polarization) and pathway identification (mTOR/STAT3), single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"34474008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In zebrafish, Plxna2 acts together with Sema6a (semaphorin 6a) to maintain eye vesicle cohesion during morphogenesis. sema6a is expressed throughout the eye vesicle while plxna2 is restricted to the ventral vesicle; knockdown of either causes loss of vesicle integrity with eye progenitors failing to enter evaginating vesicles or delaminating from the eye epithelium. Simultaneous knockdown of both sema6a and plxna2 rescues eye vesicle integrity, indicating that neutralization of Sema6a/Plxna2-mediated repulsion promotes cell-cell interactions within the tissue domain.\",\n      \"method\": \"Morpholino knockdown of plxna2 and/or sema6a in zebrafish; time-lapse microscopy; explant experiments; epistasis rescue by double knockdown\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (double knockdown rescue), time-lapse live imaging, explant experiments, multiple orthogonal methods establishing tissue-autonomous mechanism in a model organism\",\n      \"pmids\": [\"24917502\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLXNA2 (Plexin A2) is a transmembrane semaphorin receptor that mediates repulsive cell-guidance signaling: in zebrafish, Plxna2 acts with Sema6a to regulate spatially restricted repulsion that maintains eye vesicle cohesion during morphogenesis; in mammalian contexts, PLXNA2 promotes prostate cancer cell migration and invasion downstream of the TMPRSS2:ERG oncogenic fusion, and regulates microglial polarization (M1-to-M2 switch) after ischemia/reperfusion injury via mTOR/STAT3 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLXNA2 (Plexin A2) is a semaphorin co-receptor that transduces cell-guidance signals governing tissue morphogenesis, cell migration, and inflammatory cell states [#2]. During zebrafish eye morphogenesis, Plxna2 partners with the semaphorin Sema6a to mediate spatially restricted repulsion: sema6a is expressed throughout the eye vesicle while plxna2 is confined to the ventral vesicle, and genetic epistasis shows that simultaneous removal of both restores vesicle integrity, establishing that Sema6a/Plxna2 repulsion must be locally neutralized to permit cohesive cell-cell interactions within the tissue domain [#2]. In mammalian disease contexts, PLXNA2 is a direct transcriptional target of the TMPRSS2:ERG oncogenic fusion and acts dose-dependently downstream of it to drive prostate cancer cell migration and invasion, with elevated expression in metastatic relative to localized tumors [#0]. PLXNA2 also regulates microglial polarization after cerebral ischemia/reperfusion injury, where its loss shifts microglia from a pro-inflammatory M1 to an anti-inflammatory M2 state through mTOR/STAT3 signaling [#1]. The biochemical mechanism by which PLXNA2 couples semaphorin engagement to these downstream migratory and signaling outputs has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that PLXNA2 is a downstream effector of an oncogenic transcription factor fusion, linking semaphorin receptor expression to cancer cell invasiveness.\",\n      \"evidence\": \"Microarray, dose-titrated ectopic TMPRSS2:ERG expression, PLXNA2 knockdown/overexpression with migration/invasion assays, and IHC of clinical prostate cancer samples\",\n      \"pmids\": [\"23708657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No biochemical mechanism for how PLXNA2 drives migration/invasion\",\n        \"Ligand and signaling partners in prostate cancer not identified\",\n        \"Single lab; causality in metastasis not tested in vivo\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the core ligand-receptor pairing and showed that spatially restricted Sema6a/Plxna2 repulsion controls tissue cohesion during organ morphogenesis.\",\n      \"evidence\": \"Morpholino single and double knockdown with epistasis rescue, time-lapse live imaging, and explant experiments in zebrafish\",\n      \"pmids\": [\"24917502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Intracellular signaling downstream of Plxna2 not resolved\",\n        \"Established in zebrafish; mammalian morphogenetic role not tested\",\n        \"Structural basis of Sema6a-Plxna2 interaction not addressed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended PLXNA2 function to neuroinflammation, identifying mTOR/STAT3 as the pathway through which it controls microglial polarization after ischemic injury.\",\n      \"evidence\": \"PLXNA2 knockdown in MCAO/R rat model and OGD/R BV2 microglia with behavioral tests, immunofluorescence, qRT-PCR, and Western blot of M1/M2 and mTOR/STAT3 markers\",\n      \"pmids\": [\"34474008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PLXNA2 acts cell-autonomously in microglia versus via an upstream semaphorin is unresolved\",\n        \"Direct molecular link between PLXNA2 and mTOR/STAT3 not established\",\n        \"Single lab; human relevance not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical signal-transduction mechanism connecting PLXNA2 semaphorin engagement to downstream migratory and inflammatory outputs remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural or enzymatic mechanism for PLXNA2 signaling in the corpus\",\n        \"Co-receptors and cytoplasmic effectors across contexts not identified\",\n        \"Unifying model across morphogenesis, cancer, and inflammation absent\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SEMA6A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}