{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nGlypican‐5 (GPC5) is a heparan sulfate proteoglycan that plays a pivotal role in developmental processes and neural regulation. In multiple sclerosis, for example, independent replication studies have confirmed an association between variants in GPC5 and disease susceptibility, suggesting that GPC5 is an important component in central nervous system development and immune regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Developmental studies further implicate GPC5 in morphogenesis: deletion analyses in 13q syndromes have revealed that GPC5 expression in the limb bud mesenchyme contributes to proper upper limb formation, while rare copy number variants removing GPC5 are associated with neural tube defects. Moreover, mechanistic investigations have demonstrated that GPC5 enhances Sonic Hedgehog signaling—by promoting the binding of Sonic Hedgehog to its receptor Patched-1 via its highly sulfated glycosaminoglycan chains and localization to primary cilia—and that specific GPC5-containing heparan sulfate proteoglycan complexes act as co‐receptors in neural precursor proliferation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of cancer biology, GPC5 frequently emerges as a tumor suppressor. In lung adenocarcinoma, reduced expression of GPC5—often due to promoter hypermethylation or microRNA-mediated repression—correlates with increased cellular proliferation, migration, and invasion, with studies demonstrating that restoration of GPC5 inhibits tumor growth by attenuating the Wnt/β-catenin signaling pathway."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": " Similar tumor‐suppressive functions are evident in prostate cancer, where upregulation of GPC5 limits cell proliferation and epithelial–mesenchymal transition"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", as well as in pancreatic ductal adenocarcinoma, in which down‐regulation of GPC5 fosters aberrant cell growth via dysregulated Wnt signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In glioma, diminished GPC5 expression is similarly associated with enhanced tumor aggressiveness and activation of β‐catenin signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Complementary studies in oral squamous cell carcinoma have noted GPC5 colocalization with Hedgehog pathway components"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", and cellular investigations in transformed mesenchymal stem cells have further shown that GPC5 is strategically localized at primary cilia, at the leading edge of migrating cells, and within secreted extracellular vesicles—suggesting roles in modulating fibroblast growth factor signaling and cell motility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic association studies reinforce the multifaceted contribution of GPC5 to human disease. Genome‐wide analyses and replication studies have identified polymorphisms in GPC5 that are significantly associated with multiple sclerosis and other inflammatory demyelinating diseases, underscoring its role in immune regulation and central nervous system pathology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "17"}]}, {"type": "t", "text": " Further, additional investigations in diverse populations have linked specific GPC5 variants not only with demyelinating conditions such as neuromyelitis optica but also with lung cancer risk in never‐smokers, sometimes exhibiting sex‐specific effects."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "20"}]}, {"type": "t", "text": " Moreover, studies examining other low‐penetrance alleles related to carcinogenesis have implicated GPC5 variants in modifying lung cancer susceptibility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " Collectively, these genetic findings highlight GPC5 as a regulatory hub whose expression and variation influence both developmental signaling and tumorigenesis, making it a promising target for future diagnostic and therapeutic strategies.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sergio E Baranzini, Joanne Wang, Rachel A Gibson, et al. 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