{"gene":"PLXNA1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2024,"finding":"PLXNA1 recruits NRP1 to form a PLXNA1-NRP1 complex, which potentiates phosphorylation of AKT, thereby conferring enzalutamide resistance in prostate cancer cells. Inhibition of the PLXNA1-NRP1 complex with the NRP1 inhibitor EG01377 or AKT inhibitors abolished the pro-resistance phenotype.","method":"Co-immunoprecipitation (PLXNA1-NRP1 complex formation), phospho-AKT signaling assays, NRP1 inhibitor (EG01377) and AKT inhibitor treatment, loss-of-function knockdown with proliferation readout","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for complex, pharmacological inhibition, and signaling assays in single lab with multiple orthogonal methods","pmids":["39226661"],"is_preprint":false},{"year":2022,"finding":"Enzalutamide increases RUVBL1 accumulation in the cytoplasm, which enhances recruitment of CRAF to PLXNA1 and subsequent activation of the downstream MAPK pathway, promoting enzalutamide resistance in prostate cancer.","method":"Co-immunoprecipitation (CRAF–PLXNA1 interaction), co-overexpression experiments, RUVBL1 inhibitor (CB-6644) treatment, xenograft models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and pharmacological inhibition in single lab with multiple orthogonal methods","pmids":["35508542"],"is_preprint":false},{"year":2019,"finding":"PLXNA1 acts as a co-receptor with NRP1/NRP2 for SEMA3A to position olfactory/vomeronasal axons required for correct GnRH neuron migration. Combined loss of PLXNA1 and PLXNA3 (but not either alone) phenocopied the full spectrum of nasal axon and GnRH neuron defects observed in SEMA3A knockout mice, placing PLXNA1 and PLXNA3 cooperatively downstream of SEMA3A in this pathway.","method":"Genetic epistasis in mouse knockout models (Plxna1, Plxna3, Sema3a single and double knockouts); immunofluorescence of axon and GnRH neuron positioning","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double and single knockout mice, replicated across multiple genotypes and with SEMA3A null controls","pmids":["31690636"],"is_preprint":false},{"year":2019,"finding":"miR-134 directly targets PLXNA1 mRNA (verified by dual-luciferase reporter assay), and PLXNA1 silencing blocks the MAPK signaling pathway, suppressing ESCC cell proliferation, migration, invasion, and tumor metastasis.","method":"Dual-luciferase reporter assay (miR-134 targeting PLXNA1 3'UTR), siRNA knockdown of PLXNA1, MAPK pathway protein expression analysis, in vitro migration/invasion assays, in vivo xenograft","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct luciferase validation of miRNA targeting, plus loss-of-function with pathway readout, single lab","pmids":["31383552"],"is_preprint":false},{"year":2025,"finding":"A bispecific antibody (bsAb) that dimerizes PLXNA1 and NRP2 selectively mimics the tumor-suppressive signaling of SEMA3F via NRP2/PLXNA1, inhibiting phospho-AKT, oncogene expression, and cell proliferation. Structural studies showed the bsAb binds PLXNA1 and NRP2 at sites distinct from the SEMA3F-binding site but allows proper spacing for receptor complex formation.","method":"Cell-based receptor dimerization assays, phospho-AKT assays, cell proliferation assays, structural studies of bsAb–PLXNA1/NRP2 binding","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — structural data plus multiple cell-based functional assays; single lab, no in vivo confirmation reported in abstract","pmids":["41391772"],"is_preprint":false},{"year":2024,"finding":"Conditional knockdown of PLXNA1 in motor cortex layer 5 neurons in mice enhanced cortical projections to brainstem vocal motor neurons, increased functional connectivity to phonatory muscles, and widened vocal abilities, demonstrating that PLXNA1 expression in layer 5 neurons normally restricts cortico-motoneuronal projections for vocalization.","method":"Conditional in vivo knockdown (Cre-dependent) of Plxna1 in mouse motor cortex layer 5 neurons; axon tracing, electrophysiology/functional connectivity, vocal behavior assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean in vivo conditional KD with defined anatomical and behavioral phenotype, preprint, single lab, not yet peer-reviewed","pmids":["bio_10.1101_2024.10.14.618267"],"is_preprint":true},{"year":2024,"finding":"Plxna1 is identified as a receptor for the Slit3-C fragment in brown adipose tissue. Loss of Plxna1 impaired sympathetic innervation and cold-induced neurite expansion in BAT, demonstrating an essential role for PLXNA1 in sympathetic innervation downstream of Slit3-C.","method":"Receptor-ligand binding assay (Slit3-C to Plxna1), in vivo loss-of-function (Plxna1 knockout/knockdown), sympathetic innervation and cold-stimulation assays in BAT","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo loss-of-function with defined innervation phenotype and binding identification; preprint, single lab, not peer-reviewed","pmids":["bio_10.1101_2024.09.24.613949"],"is_preprint":true},{"year":2021,"finding":"Morpholino knockdown of plxna1a and plxna1b in zebrafish disrupted development of the central nervous system and eye, establishing an embryonic role for these orthologs in CNS and eye development.","method":"Morpholino knockdown in zebrafish embryos; phenotypic analysis of CNS and eye development","journal":"Genetics in medicine : official journal of the American College of Medical Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function in zebrafish with defined developmental phenotype; two paralogs tested; single lab","pmids":["34054129"],"is_preprint":false},{"year":2024,"finding":"PLXNA1 localizes to extracellular vesicles (EVs) with high EV-sorting ability. A truncated form of PLXNA1 retains this EV-sorting capacity and can serve as a scaffold for fusion expression of proteins of interest on the outer surface or in the lumen of EVs.","method":"EV fractionation, genetic fusion constructs, EV protein loading assays (Western blot/flow cytometry)","journal":"Journal of extracellular vesicles","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single-method protein localization to EVs without broader functional validation of PLXNA1 mechanism","pmids":["39508411"],"is_preprint":false}],"current_model":"PLXNA1 (Plexin-A1) is a transmembrane axon guidance receptor that acts as a co-receptor with neuropilins (NRP1/NRP2) for class 3 semaphorins (SEMA3A, SEMA3F); cooperates with PLXNA3 downstream of SEMA3A to pattern nasal axons guiding GnRH neuron migration; in the CNS it restricts cortico-motoneuronal projections; in cancer contexts, PLXNA1 forms a complex with NRP1 to activate AKT signaling and associates with CRAF (recruited by RUVBL1) to activate MAPK signaling, both promoting enzalutamide resistance in prostate cancer; and in brown adipose tissue it functions as a receptor for the Slit3-C fragment to mediate sympathetic innervation."},"narrative":{"mechanistic_narrative":"PLXNA1 (Plexin-A1) is a transmembrane semaphorin co-receptor that, together with neuropilins, transduces guidance cues controlling axon positioning and neuronal connectivity [PMID:31690636]. In the developing nervous system, PLXNA1 acts cooperatively with PLXNA3 downstream of SEMA3A to position olfactory/vomeronasal axons required for correct GnRH neuron migration, with combined loss of both plexins phenocopying the SEMA3A-null defect [PMID:31690636], and it restricts cortico-motoneuronal projections in motor cortex layer 5 neurons to constrain vocal motor connectivity [PMID:bio_10.1101_2024.10.14.618267]. PLXNA1 also serves as a receptor for the Slit3-C fragment to drive sympathetic innervation of brown adipose tissue [PMID:bio_10.1101_2024.09.24.613949], and zebrafish ortholog knockdown disrupts CNS and eye development [PMID:34054129]. In cancer, PLXNA1 functions through two signaling arms: it recruits NRP1 to form a PLXNA1-NRP1 complex that potentiates AKT phosphorylation [PMID:39226661], and RUVBL1-dependent recruitment of CRAF to PLXNA1 activates MAPK signaling [PMID:35508542], with both axes promoting enzalutamide resistance in prostate cancer; PLXNA1 silencing conversely blocks MAPK signaling and suppresses esophageal carcinoma proliferation and metastasis [PMID:31383552]. Engineered dimerization of PLXNA1 with NRP2 reconstitutes tumor-suppressive SEMA3F-like signaling that inhibits AKT and proliferation [PMID:41391772].","teleology":[{"year":2019,"claim":"Established that PLXNA1 acts cooperatively with PLXNA3 as a SEMA3A co-receptor to position nasal axons guiding GnRH neuron migration, resolving which plexins transduce this neuropilin-dependent cue in vivo.","evidence":"Genetic epistasis with single and double Plxna1/Plxna3 knockouts against Sema3a-null mice, with immunofluorescence of axon and GnRH neuron positioning","pmids":["31690636"],"confidence":"High","gaps":["Does not resolve the cytoplasmic signaling cascade downstream of PLXNA1 in this pathway","Functional redundancy boundaries with other plexins not fully mapped"]},{"year":2019,"claim":"Linked PLXNA1 to oncogenic MAPK signaling by showing miR-134 directly represses PLXNA1 and that PLXNA1 is required for tumor cell proliferation and metastasis.","evidence":"Dual-luciferase reporter assay for miR-134 targeting, siRNA knockdown with MAPK readout, migration/invasion assays and xenograft in esophageal carcinoma","pmids":["31383552"],"confidence":"Medium","gaps":["Direct upstream ligand/receptor partner driving MAPK in this context not defined","Mechanism connecting PLXNA1 to MAPK pathway not established here"]},{"year":2021,"claim":"Demonstrated an embryonic requirement for PLXNA1 orthologs in CNS and eye development, extending its role beyond specific axon guidance circuits.","evidence":"Morpholino knockdown of plxna1a and plxna1b in zebrafish embryos with developmental phenotyping","pmids":["34054129"],"confidence":"Medium","gaps":["Morpholino specificity not cross-validated by mutant alleles","Molecular pathway underlying the developmental defect unknown"]},{"year":2022,"claim":"Identified a RUVBL1-CRAF-PLXNA1 axis activating MAPK as a mechanism of acquired enzalutamide resistance, explaining how PLXNA1 couples to RAF signaling.","evidence":"Co-immunoprecipitation of CRAF-PLXNA1, co-overexpression, RUVBL1 inhibitor (CB-6644) treatment, and xenograft models in prostate cancer","pmids":["35508542"],"confidence":"Medium","gaps":["Whether CRAF binds PLXNA1 directly or via intermediaries not resolved","Single-lab Co-IP without orthogonal interaction structure"]},{"year":2024,"claim":"Defined a parallel PLXNA1-NRP1 complex that potentiates AKT activation to drive enzalutamide resistance, distinguishing an AKT arm from the MAPK arm of PLXNA1 oncogenic signaling.","evidence":"Reciprocal Co-IP of PLXNA1-NRP1, phospho-AKT assays, NRP1 inhibitor (EG01377) and AKT inhibitor treatment, knockdown with proliferation readout in prostate cancer cells","pmids":["39226661"],"confidence":"Medium","gaps":["Ligand initiating the PLXNA1-NRP1-AKT axis in this context not identified","Relationship between the AKT and MAPK arms not integrated"]},{"year":2024,"claim":"Showed via conditional knockdown that PLXNA1 in layer 5 motor cortex neurons normally restricts cortico-motoneuronal projections, controlling vocal motor connectivity.","evidence":"Cre-dependent in vivo knockdown of Plxna1 in mouse motor cortex layer 5 neurons; axon tracing, functional connectivity electrophysiology, vocal behavior assays (preprint)","pmids":["bio_10.1101_2024.10.14.618267"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Upstream guidance cue mediating projection restriction not defined"]},{"year":2024,"claim":"Identified PLXNA1 as a receptor for the Slit3-C fragment required for sympathetic innervation of brown adipose tissue, expanding its ligand repertoire beyond semaphorins.","evidence":"Slit3-C-to-Plxna1 receptor-ligand binding assay and in vivo Plxna1 loss-of-function with innervation and cold-stimulation phenotyping in BAT (preprint)","pmids":["bio_10.1101_2024.09.24.613949"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Whether a co-receptor or neuropilin is required for Slit3-C signaling unknown","Downstream signaling not characterized"]},{"year":2024,"claim":"Reported that PLXNA1 has high extracellular-vesicle-sorting ability and can serve as an engineerable EV scaffold.","evidence":"EV fractionation, genetic fusion constructs, and EV protein-loading assays","pmids":["39508411"],"confidence":"Low","gaps":["Single-method localization without broader mechanistic validation","Endogenous biological significance of PLXNA1 EV sorting unknown"]},{"year":2025,"claim":"Demonstrated that engineered PLXNA1-NRP2 dimerization reconstitutes tumor-suppressive SEMA3F-like signaling, establishing that receptor geometry dictates whether PLXNA1 output is suppressive or oncogenic.","evidence":"Bispecific antibody dimerizing PLXNA1 and NRP2, phospho-AKT and proliferation assays, and structural studies of bsAb binding sites","pmids":["41391772"],"confidence":"Medium","gaps":["No in vivo confirmation reported","Endogenous SEMA3F/NRP2/PLXNA1 signaling thresholds not quantified"]},{"year":null,"claim":"How PLXNA1 cytoplasmic output is switched between tumor-suppressive (AKT-inhibitory) and oncogenic (AKT/MAPK-activating) modes across ligand and co-receptor contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking neuropilin/co-receptor identity to downstream signaling sign","Direct enzymatic activity of PLXNA1 not defined in the corpus","Structural basis of context-dependent signaling not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,6]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,5,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,3]}],"complexes":["PLXNA1-NRP1 complex","PLXNA1-NRP2 complex"],"partners":["NRP1","NRP2","PLXNA3","CRAF","RUVBL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UIW2","full_name":"Plexin-A1","aliases":["Semaphorin receptor NOV"],"length_aa":1896,"mass_kda":211.1,"function":"Coreceptor for SEMA3A, SEMA3C, SEMA3F and SEMA6D. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance, invasive growth and cell migration. 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. Acts as coreceptor of TREM2 for SEMA6D in dendritic cells and is involved in the generation of immune responses and skeletal homeostasis","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UIW2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLXNA1","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/PLXNA1","total_profiled":1310},"omim":[{"mim_id":"620997","title":"SEMAPHORIN 3G; SEMA3G","url":"https://www.omim.org/entry/620997"},{"mim_id":"619955","title":"DWORSCHAK-PUNETHA NEURODEVELOPMENTAL SYNDROME; DWOPNED","url":"https://www.omim.org/entry/619955"},{"mim_id":"607414","title":"FEZ FAMILY ZINC FINGER PROTEIN 2; FEZF2","url":"https://www.omim.org/entry/607414"},{"mim_id":"601471","title":"FACIAL PARESIS, HEREDITARY CONGENITAL, 1; HCFP1","url":"https://www.omim.org/entry/601471"},{"mim_id":"601055","title":"PLEXIN A1; PLXNA1","url":"https://www.omim.org/entry/601055"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PLXNA1"},"hgnc":{"alias_symbol":["NOV"],"prev_symbol":["PLXN1"]},"alphafold":{"accession":"Q9UIW2","domains":[{"cath_id":"2.130.10.10","chopping":"232-480","consensus_level":"medium","plddt":88.8857,"start":232,"end":480},{"cath_id":"2.60.40.10","chopping":"520-673","consensus_level":"medium","plddt":90.3084,"start":520,"end":673},{"cath_id":"2.60.40","chopping":"709-853","consensus_level":"medium","plddt":87.0274,"start":709,"end":853},{"cath_id":"2.60.40.10","chopping":"866-1043","consensus_level":"medium","plddt":92.3583,"start":866,"end":1043},{"cath_id":"2.60.40.10","chopping":"1048-1148","consensus_level":"medium","plddt":90.065,"start":1048,"end":1148},{"cath_id":"2.60.40.10","chopping":"1152-1239","consensus_level":"medium","plddt":80.8148,"start":1152,"end":1239},{"cath_id":"1.10.506.10","chopping":"1302-1333_1435-1479_1679-1840","consensus_level":"medium","plddt":86.2503,"start":1302,"end":1840},{"cath_id":"-","chopping":"1338-1399_1846-1896","consensus_level":"medium","plddt":87.6596,"start":1338,"end":1896},{"cath_id":"3.10.20.90","chopping":"1498-1604_1651-1655","consensus_level":"medium","plddt":84.9352,"start":1498,"end":1655}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIW2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIW2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIW2-F1-predicted_aligned_error_v6.png","plddt_mean":84.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLXNA1","jax_strain_url":"https://www.jax.org/strain/search?query=PLXNA1"},"sequence":{"accession":"Q9UIW2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UIW2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UIW2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIW2"}},"corpus_meta":[{"pmid":"34054129","id":"PMC_34054129","title":"Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies.","date":"2021","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34054129","citation_count":34,"is_preprint":false},{"pmid":"32692763","id":"PMC_32692763","title":"Circular RNA expression profiling reveals that circ-PLXNA1 functions in duck adipocyte differentiation.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32692763","citation_count":28,"is_preprint":false},{"pmid":"35508542","id":"PMC_35508542","title":"RUVBL1 promotes enzalutamide resistance of prostate tumors through the PLXNA1-CRAF-MAPK pathway.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/35508542","citation_count":25,"is_preprint":false},{"pmid":"31383552","id":"PMC_31383552","title":"MicroRNA-134 prevents the progression of esophageal squamous cell carcinoma via the PLXNA1-mediated MAPK signalling pathway.","date":"2019","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/31383552","citation_count":24,"is_preprint":false},{"pmid":"31690636","id":"PMC_31690636","title":"PLXNA1 and PLXNA3 cooperate to pattern the nasal axons that guide gonadotropin-releasing hormone neurons.","date":"2019","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/31690636","citation_count":22,"is_preprint":false},{"pmid":"30467832","id":"PMC_30467832","title":"Prevalence and associated phenotypes of PLXNA1 variants in normosmic and anosmic idiopathic hypogonadotropic hypogonadism.","date":"2018","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30467832","citation_count":21,"is_preprint":false},{"pmid":"39226661","id":"PMC_39226661","title":"PLXNA1 confers enzalutamide resistance in prostate cancer via AKT signaling pathway.","date":"2024","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/39226661","citation_count":13,"is_preprint":false},{"pmid":"39508411","id":"PMC_39508411","title":"PlexinA1 (PLXNA1) as a novel scaffold protein for the engineering of extracellular vesicles.","date":"2024","source":"Journal of extracellular vesicles","url":"https://pubmed.ncbi.nlm.nih.gov/39508411","citation_count":12,"is_preprint":false},{"pmid":"34415653","id":"PMC_34415653","title":"Neuropathological Findings in a Case of Parkinsonism and Developmental Delay Associated with a Monoallelic Variant in PLXNA1.","date":"2021","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/34415653","citation_count":10,"is_preprint":false},{"pmid":"40318008","id":"PMC_40318008","title":"Boric Acid Induces Oxidative Damage and Apoptosis Through SEMA3A/PLXNA1/NRP1 Signalling Pathway in U251 Glioblastoma Cell.","date":"2025","source":"Journal of cellular and molecular 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University","url":"https://pubmed.ncbi.nlm.nih.gov/38081609","citation_count":2,"is_preprint":false},{"pmid":"35852441","id":"PMC_35852441","title":"Rare variant screening and burden analysis of PLXNA1 in Parkinson's disease.","date":"2022","source":"European journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35852441","citation_count":1,"is_preprint":false},{"pmid":"40645385","id":"PMC_40645385","title":"Integrating multi-omics analysis to uncover the impact of PLXNA1 on the progression of esophageal cancer cells.","date":"2025","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40645385","citation_count":0,"is_preprint":false},{"pmid":"41391772","id":"PMC_41391772","title":"A bispecific antibody designed to act as a NRP2/PLXNA1 agonist mimics anticancer activity of SEMA3F.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41391772","citation_count":0,"is_preprint":false},{"pmid":"41424197","id":"PMC_41424197","title":"A Case Report of PLXNA1-Related Dworschak-Punetha Neurodevelopmental Disorder With Pachygyria and Polymicrogyria.","date":"2025","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/41424197","citation_count":0,"is_preprint":false},{"pmid":"41657556","id":"PMC_41657556","title":"Maternal mixed UPD3 and a homozygous PLXNA1 c.2497G>C variant in a fetus with severe anomalies.","date":"2026","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41657556","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.14.618267","title":"Enhancing cortico-motoneuronal projections for vocalization in mice","date":"2024-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.14.618267","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.24.613949","title":"Slit3 Fragments Orchestrate Neurovascular Expansion and Thermogenesis in Brown Adipose Tissue","date":"2024-09-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.24.613949","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11476,"output_tokens":2459,"usd":0.035657,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9571,"output_tokens":3417,"usd":0.06664,"stage2_stop_reason":"end_turn"},"total_usd":0.102297,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"PLXNA1 recruits NRP1 to form a PLXNA1-NRP1 complex, which potentiates phosphorylation of AKT, thereby conferring enzalutamide resistance in prostate cancer cells. Inhibition of the PLXNA1-NRP1 complex with the NRP1 inhibitor EG01377 or AKT inhibitors abolished the pro-resistance phenotype.\",\n      \"method\": \"Co-immunoprecipitation (PLXNA1-NRP1 complex formation), phospho-AKT signaling assays, NRP1 inhibitor (EG01377) and AKT inhibitor treatment, loss-of-function knockdown with proliferation readout\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for complex, pharmacological inhibition, and signaling assays in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39226661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Enzalutamide increases RUVBL1 accumulation in the cytoplasm, which enhances recruitment of CRAF to PLXNA1 and subsequent activation of the downstream MAPK pathway, promoting enzalutamide resistance in prostate cancer.\",\n      \"method\": \"Co-immunoprecipitation (CRAF–PLXNA1 interaction), co-overexpression experiments, RUVBL1 inhibitor (CB-6644) treatment, xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and pharmacological inhibition in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35508542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PLXNA1 acts as a co-receptor with NRP1/NRP2 for SEMA3A to position olfactory/vomeronasal axons required for correct GnRH neuron migration. Combined loss of PLXNA1 and PLXNA3 (but not either alone) phenocopied the full spectrum of nasal axon and GnRH neuron defects observed in SEMA3A knockout mice, placing PLXNA1 and PLXNA3 cooperatively downstream of SEMA3A in this pathway.\",\n      \"method\": \"Genetic epistasis in mouse knockout models (Plxna1, Plxna3, Sema3a single and double knockouts); immunofluorescence of axon and GnRH neuron positioning\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double and single knockout mice, replicated across multiple genotypes and with SEMA3A null controls\",\n      \"pmids\": [\"31690636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-134 directly targets PLXNA1 mRNA (verified by dual-luciferase reporter assay), and PLXNA1 silencing blocks the MAPK signaling pathway, suppressing ESCC cell proliferation, migration, invasion, and tumor metastasis.\",\n      \"method\": \"Dual-luciferase reporter assay (miR-134 targeting PLXNA1 3'UTR), siRNA knockdown of PLXNA1, MAPK pathway protein expression analysis, in vitro migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct luciferase validation of miRNA targeting, plus loss-of-function with pathway readout, single lab\",\n      \"pmids\": [\"31383552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A bispecific antibody (bsAb) that dimerizes PLXNA1 and NRP2 selectively mimics the tumor-suppressive signaling of SEMA3F via NRP2/PLXNA1, inhibiting phospho-AKT, oncogene expression, and cell proliferation. Structural studies showed the bsAb binds PLXNA1 and NRP2 at sites distinct from the SEMA3F-binding site but allows proper spacing for receptor complex formation.\",\n      \"method\": \"Cell-based receptor dimerization assays, phospho-AKT assays, cell proliferation assays, structural studies of bsAb–PLXNA1/NRP2 binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structural data plus multiple cell-based functional assays; single lab, no in vivo confirmation reported in abstract\",\n      \"pmids\": [\"41391772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Conditional knockdown of PLXNA1 in motor cortex layer 5 neurons in mice enhanced cortical projections to brainstem vocal motor neurons, increased functional connectivity to phonatory muscles, and widened vocal abilities, demonstrating that PLXNA1 expression in layer 5 neurons normally restricts cortico-motoneuronal projections for vocalization.\",\n      \"method\": \"Conditional in vivo knockdown (Cre-dependent) of Plxna1 in mouse motor cortex layer 5 neurons; axon tracing, electrophysiology/functional connectivity, vocal behavior assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean in vivo conditional KD with defined anatomical and behavioral phenotype, preprint, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.10.14.618267\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Plxna1 is identified as a receptor for the Slit3-C fragment in brown adipose tissue. Loss of Plxna1 impaired sympathetic innervation and cold-induced neurite expansion in BAT, demonstrating an essential role for PLXNA1 in sympathetic innervation downstream of Slit3-C.\",\n      \"method\": \"Receptor-ligand binding assay (Slit3-C to Plxna1), in vivo loss-of-function (Plxna1 knockout/knockdown), sympathetic innervation and cold-stimulation assays in BAT\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo loss-of-function with defined innervation phenotype and binding identification; preprint, single lab, not peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.09.24.613949\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Morpholino knockdown of plxna1a and plxna1b in zebrafish disrupted development of the central nervous system and eye, establishing an embryonic role for these orthologs in CNS and eye development.\",\n      \"method\": \"Morpholino knockdown in zebrafish embryos; phenotypic analysis of CNS and eye development\",\n      \"journal\": \"Genetics in medicine : official journal of the American College of Medical Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function in zebrafish with defined developmental phenotype; two paralogs tested; single lab\",\n      \"pmids\": [\"34054129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PLXNA1 localizes to extracellular vesicles (EVs) with high EV-sorting ability. A truncated form of PLXNA1 retains this EV-sorting capacity and can serve as a scaffold for fusion expression of proteins of interest on the outer surface or in the lumen of EVs.\",\n      \"method\": \"EV fractionation, genetic fusion constructs, EV protein loading assays (Western blot/flow cytometry)\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single-method protein localization to EVs without broader functional validation of PLXNA1 mechanism\",\n      \"pmids\": [\"39508411\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLXNA1 (Plexin-A1) is a transmembrane axon guidance receptor that acts as a co-receptor with neuropilins (NRP1/NRP2) for class 3 semaphorins (SEMA3A, SEMA3F); cooperates with PLXNA3 downstream of SEMA3A to pattern nasal axons guiding GnRH neuron migration; in the CNS it restricts cortico-motoneuronal projections; in cancer contexts, PLXNA1 forms a complex with NRP1 to activate AKT signaling and associates with CRAF (recruited by RUVBL1) to activate MAPK signaling, both promoting enzalutamide resistance in prostate cancer; and in brown adipose tissue it functions as a receptor for the Slit3-C fragment to mediate sympathetic innervation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLXNA1 (Plexin-A1) is a transmembrane semaphorin co-receptor that, together with neuropilins, transduces guidance cues controlling axon positioning and neuronal connectivity [#2]. In the developing nervous system, PLXNA1 acts cooperatively with PLXNA3 downstream of SEMA3A to position olfactory/vomeronasal axons required for correct GnRH neuron migration, with combined loss of both plexins phenocopying the SEMA3A-null defect [#2], and it restricts cortico-motoneuronal projections in motor cortex layer 5 neurons to constrain vocal motor connectivity [#5]. PLXNA1 also serves as a receptor for the Slit3-C fragment to drive sympathetic innervation of brown adipose tissue [#6], and zebrafish ortholog knockdown disrupts CNS and eye development [#7]. In cancer, PLXNA1 functions through two signaling arms: it recruits NRP1 to form a PLXNA1-NRP1 complex that potentiates AKT phosphorylation [#0], and RUVBL1-dependent recruitment of CRAF to PLXNA1 activates MAPK signaling [#1], with both axes promoting enzalutamide resistance in prostate cancer; PLXNA1 silencing conversely blocks MAPK signaling and suppresses esophageal carcinoma proliferation and metastasis [#3]. Engineered dimerization of PLXNA1 with NRP2 reconstitutes tumor-suppressive SEMA3F-like signaling that inhibits AKT and proliferation [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that PLXNA1 acts cooperatively with PLXNA3 as a SEMA3A co-receptor to position nasal axons guiding GnRH neuron migration, resolving which plexins transduce this neuropilin-dependent cue in vivo.\",\n      \"evidence\": \"Genetic epistasis with single and double Plxna1/Plxna3 knockouts against Sema3a-null mice, with immunofluorescence of axon and GnRH neuron positioning\",\n      \"pmids\": [\"31690636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve the cytoplasmic signaling cascade downstream of PLXNA1 in this pathway\", \"Functional redundancy boundaries with other plexins not fully mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked PLXNA1 to oncogenic MAPK signaling by showing miR-134 directly represses PLXNA1 and that PLXNA1 is required for tumor cell proliferation and metastasis.\",\n      \"evidence\": \"Dual-luciferase reporter assay for miR-134 targeting, siRNA knockdown with MAPK readout, migration/invasion assays and xenograft in esophageal carcinoma\",\n      \"pmids\": [\"31383552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct upstream ligand/receptor partner driving MAPK in this context not defined\", \"Mechanism connecting PLXNA1 to MAPK pathway not established here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated an embryonic requirement for PLXNA1 orthologs in CNS and eye development, extending its role beyond specific axon guidance circuits.\",\n      \"evidence\": \"Morpholino knockdown of plxna1a and plxna1b in zebrafish embryos with developmental phenotyping\",\n      \"pmids\": [\"34054129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino specificity not cross-validated by mutant alleles\", \"Molecular pathway underlying the developmental defect unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a RUVBL1-CRAF-PLXNA1 axis activating MAPK as a mechanism of acquired enzalutamide resistance, explaining how PLXNA1 couples to RAF signaling.\",\n      \"evidence\": \"Co-immunoprecipitation of CRAF-PLXNA1, co-overexpression, RUVBL1 inhibitor (CB-6644) treatment, and xenograft models in prostate cancer\",\n      \"pmids\": [\"35508542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CRAF binds PLXNA1 directly or via intermediaries not resolved\", \"Single-lab Co-IP without orthogonal interaction structure\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a parallel PLXNA1-NRP1 complex that potentiates AKT activation to drive enzalutamide resistance, distinguishing an AKT arm from the MAPK arm of PLXNA1 oncogenic signaling.\",\n      \"evidence\": \"Reciprocal Co-IP of PLXNA1-NRP1, phospho-AKT assays, NRP1 inhibitor (EG01377) and AKT inhibitor treatment, knockdown with proliferation readout in prostate cancer cells\",\n      \"pmids\": [\"39226661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand initiating the PLXNA1-NRP1-AKT axis in this context not identified\", \"Relationship between the AKT and MAPK arms not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed via conditional knockdown that PLXNA1 in layer 5 motor cortex neurons normally restricts cortico-motoneuronal projections, controlling vocal motor connectivity.\",\n      \"evidence\": \"Cre-dependent in vivo knockdown of Plxna1 in mouse motor cortex layer 5 neurons; axon tracing, functional connectivity electrophysiology, vocal behavior assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.10.14.618267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Upstream guidance cue mediating projection restriction not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified PLXNA1 as a receptor for the Slit3-C fragment required for sympathetic innervation of brown adipose tissue, expanding its ligand repertoire beyond semaphorins.\",\n      \"evidence\": \"Slit3-C-to-Plxna1 receptor-ligand binding assay and in vivo Plxna1 loss-of-function with innervation and cold-stimulation phenotyping in BAT (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.09.24.613949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Whether a co-receptor or neuropilin is required for Slit3-C signaling unknown\", \"Downstream signaling not characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reported that PLXNA1 has high extracellular-vesicle-sorting ability and can serve as an engineerable EV scaffold.\",\n      \"evidence\": \"EV fractionation, genetic fusion constructs, and EV protein-loading assays\",\n      \"pmids\": [\"39508411\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-method localization without broader mechanistic validation\", \"Endogenous biological significance of PLXNA1 EV sorting unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that engineered PLXNA1-NRP2 dimerization reconstitutes tumor-suppressive SEMA3F-like signaling, establishing that receptor geometry dictates whether PLXNA1 output is suppressive or oncogenic.\",\n      \"evidence\": \"Bispecific antibody dimerizing PLXNA1 and NRP2, phospho-AKT and proliferation assays, and structural studies of bsAb binding sites\",\n      \"pmids\": [\"41391772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo confirmation reported\", \"Endogenous SEMA3F/NRP2/PLXNA1 signaling thresholds not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PLXNA1 cytoplasmic output is switched between tumor-suppressive (AKT-inhibitory) and oncogenic (AKT/MAPK-activating) modes across ligand and co-receptor contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking neuropilin/co-receptor identity to downstream signaling sign\", \"Direct enzymatic activity of PLXNA1 not defined in the corpus\", \"Structural basis of context-dependent signaling not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 5, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"complexes\": [\"PLXNA1-NRP1 complex\", \"PLXNA1-NRP2 complex\"],\n    \"partners\": [\"NRP1\", \"NRP2\", \"PLXNA3\", \"CRAF\", \"RUVBL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}