{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPLXNA4 is a multifunctional receptor that mediates semaphorin‐driven signaling important for angiogenesis and tumor cell proliferation. For instance, in endothelial and glioblastoma cells, PLXNA4 directly binds sema6A and sema6B, associates with neuropilins, and forms complexes with other plexins to modulate actin cytoskeletal reorganization and enhance growth factor–dependent signals, such as those triggered by VEGF and bFGF. These pathways not only regulate cell contraction and proliferation but also point to PLXNA4 as a promising target for anti‐angiogenic and anti‐tumor strategies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in vascular biology, PLXNA4 participates in immune regulation. Recent studies demonstrated that an agonistic B7‐H4 fusion protein exerts anti‐inflammatory effects through binding to Sema3a, which in turn bridges with a receptor complex formed by neuropilin-1 and PLXNA4. This interaction leads to enhanced PTEN phosphorylation and an increase in regulatory CD4+ T cell function, thereby contributing to immune homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nIn the central nervous system, PLXNA4 functions as a high-affinity receptor for clusterin and is genetically linked to Alzheimer disease (AD). Genome-wide approaches have implicated PLXNA4 variants in AD susceptibility, and experimental studies have shown that reduced PLXNA4 levels are associated with memory deficits and altered brain microstructure. These findings support a model in which impaired PLXNA4-mediated signaling disrupts neural homeostasis and contributes to cognitive decline."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nPLXNA4 also plays a critical role in neural development and axonal guidance. In glioblastoma and mesenchymal stem cell models, PLXNA4 forms complexes with other plexins such as plexin-D1 to transduce signals from various class-3 semaphorins. This activity modulates cytoskeletal dynamics essential for directed cell migration and neural differentiation, with evidence pointing to a SEMA3A–PLXNA4-dependent FYN kinase pathway in neuronal lineage commitment."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, rare non-synonymous variants in PLXNA4 have been identified in familial Parkinson’s disease, suggesting that alterations in axonal guidance mechanisms mediated by PLXNA4 may extend to neurodegenerative disorders beyond AD."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nGenome-wide analyses integrating proteomics and genetic data have further associated PLXNA4 locus variants and decreased protein levels with an increased risk of pulmonary embolism. Such findings imply that PLXNA4 contributes to vascular integrity and the regulation of thromboembolic events, a role that is also under investigation in the context of acute lung injury in COVID-19."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, broad genomic screens for injury-related biomarkers have included PLXNA4 among candidate genes linked to concussion risk, highlighting its potential involvement in the neurobiological responses to traumatic brain injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}]}]}]}]}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Boaz Kigel, Noa Rabinowicz, Asya Varshavsky, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Identification of plexin A4 as a novel clusterin receptor links two Alzheimer's disease risk genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddw188"}], "href": "https://doi.org/10.1093/hmg/ddw188"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27378688"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27378688"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Tatyana Smolkin, Inbal Nir-Zvi, Nerri Duvshani, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Complexes of plexin-A4 and plexin-D1 convey semaphorin-3C signals to induce cytoskeletal collapse in the absence of neuropilins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.208298"}], "href": "https://doi.org/10.1242/jcs.208298"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29661844"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29661844"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Hyunjin Cho, Hee-Jung Park, Young-Kwon Seo "}, {"type": "b", "children": [{"type": "t", "text": "Induction of "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "PLXNA4"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Gene during Neural Differentiation in Human Umbilical-Cord-Derived Mesenchymal Stem Cells by Low-Intensity Sub-Sonic Vibration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms23031522"}], "href": "https://doi.org/10.3390/ijms23031522"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35163445"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35163445"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Eva C Schulte, Immanuel Stahl, Darina Czamara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rare variants in PLXNA4 and Parkinson's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0079145"}], "href": "https://doi.org/10.1371/journal.pone.0079145"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24244438"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24244438"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Misbah Razzaq, Maria Jesus Iglesias, Manal Ibrahim-Kosta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An artificial neural network approach integrating plasma proteomics and genetic data identifies PLXNA4 as a new susceptibility locus for pulmonary embolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-021-93390-7"}], "href": "https://doi.org/10.1038/s41598-021-93390-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34234248"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34234248"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Stuart K Kim, Megan D Roche, Michael Fredericson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A Genome-wide Association Study for Concussion Risk."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Sci Sports Exerc (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1249/MSS.0000000000002529"}], "href": "https://doi.org/10.1249/MSS.0000000000002529"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33017352"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33017352"}]}]}]}