{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPLXNA1 functions as a critical receptor in developmental signaling pathways, especially in the nervous system. Acting as a receptor for class‐3 semaphorins, it regulates axon guidance, neurite outgrowth, and the migration of gonadotropin‐releasing hormone (GnRH) neurons during embryogenesis. Disruption of PLXNA1 signaling, including alterations in Fyn‐mediated tyrosine phosphorylation and transmembrane domain interactions, has been implicated in abnormal forebrain connectivity, defective olfactory system development, and associated clinical syndromes such as Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. In addition, genetic variants in PLXNA1 have been linked to altered corpus callosum microstructure and even parkinsonism, underscoring its diverse roles in neural development and function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer contexts, PLXNA1 emerges as a multifaceted regulator of tumor cell behavior. In breast carcinoma, its engagement in an autocrine semaphorin-3A/NP1/PLXNA1 inhibitory loop impedes chemotaxis—an effect that can be negated by vascular endothelial growth factor (VEGF)–mediated competition. In various malignancies including mesothelioma, pancreatic cancer, gastric carcinoma, hepatocellular carcinoma, and prostate cancer, aberrant PLXNA1 signaling fosters oncogenic processes by enhancing cell survival, proliferation, migration, and invasion via downstream pathways such as Rho-GTPase, MAPK, and AKT. Furthermore, chronic stress and tumor microenvironment cues appear to modulate PLXNA1 expression, thereby further promoting tumor progression and resistance to therapies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "16"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the mechanistic level, detailed studies have revealed that PLXNA1 signal transduction is critically dependent on its ability to dimerize and engage in receptor complexes. Molecular simulations have demonstrated that specific sequence motifs (GxxxG) in its transmembrane domain mediate homodimerization and heterodimerization with neuropilins, which are essential for downstream signaling. This receptor complex formation plays a crucial role not only in developmental processes but also in mediating apoptotic responses in immune cells such as macrophages via semaphorin-3A, thereby extending the functional repertoire of PLXNA1 into immune regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ""}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michel Belyk, Shelly Jo Kraft, Steven Brown "}, {"type": "b", "children": [{"type": "t", "text": "PlexinA polymorphisms mediate the developmental trajectory of human corpus callosum microstructure."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hum Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/jhg.2014.107"}], "href": "https://doi.org/10.1038/jhg.2014.107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25518740"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25518740"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Séverine Marcos, Carine Monnier, Xavier Rovira, et al. 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