{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRepulsive guidance molecule‐a (RGMa) is a multifunctional, glycosylphosphatidylinositol‐anchored protein that was initially characterized for its pivotal role in neural development. It guides growing axons and regulates growth cone dynamics by engaging its receptor neogenin and activating RhoA‐dependent pathways, thereby orchestrating proper laminar patterning, neural tube closure, and precise neuronal circuit formation. In addition, RGMa functions as a bone morphogenetic protein (BMP) co‐receptor to modulate intracellular Smad signaling, further influencing neuronal differentiation and migration. Its expression is tightly regulated during embryogenesis and extends to non‐neuronal tissues such as the developing gut and retina, underscoring its broad developmental impact."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its developmental functions, RGMa exerts critical roles in the mature central nervous system and the immune system. In various experimental models of neurological disorders—including multiple sclerosis, spinal cord injury, and even amyotrophic lateral sclerosis—RGMa contributes to axonal retraction, inhibition of regeneration, and neuroinflammation by modulating T‐cell adhesion, dendritic cell activation, and leukocyte chemotaxis. Molecular mechanisms underlying these effects involve the selective engagement of distinct type II BMP receptors and downstream effectors such as Rho kinase, with RGMa–neogenin interactions proving central to its signaling. Moreover, its binding domain has been precisely mapped, and the disruption of RGMa signaling (for example, with neutralizing antibodies) alleviates inflammatory responses and promotes functional recovery."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "19"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in neurodevelopment and CNS inflammation, RGMa is increasingly implicated in a variety of diverse pathophysiological processes. Altered RGMa expression affects adult neurogenesis and synaptogenesis, while its modulation in non‐neuronal tissues has been linked to skeletal muscle cell fusion, vascular smooth muscle cell dedifferentiation in atherosclerosis, and even tumor suppressor activity in breast cancer. Recent evidence also suggests that RGMa may regulate neuronal energy metabolism under ischemia–reperfusion injury by influencing glycolytic flux and protein deubiquitination processes. Collectively, these multifaceted actions highlight RGMa as an attractive therapeutic target for a broad spectrum of disorders ranging from neuroinflammatory and neurodegenerative diseases to aberrant tissue remodeling and metabolic dysregulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "29"}]}, {"type": "t", "text": ""}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jens Schmidtmer, Dieter Engelkamp "}, {"type": "b", "children": [{"type": "t", "text": "Isolation and expression pattern of three mouse homologues of chick Rgm."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene Expr Patterns (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s1567-133x(03)00144-3"}], "href": "https://doi.org/10.1016/s1567-133x(03"}, {"type": "t", "text": "00144-3) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14678836"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14678836"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Henriette Brinks, Sabine Conrad, Johannes Vogt, et al. 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