{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Fibroblast growth factor 9 (FGF9) is a multifunctional signaling molecule whose actions span numerous developmental and pathological contexts. In the developing gonad, FGF9 is essential for male sex determination. Acting in a feed‐forward loop with SOX9 and opposing ovarian signals such as WNT4, FGF9 stimulates the proliferation of Sertoli progenitors, promotes nuclear localization of FGFR2 in Sertoli cell precursors, and is required to “tip the balance” toward testicular development – its loss resulting in XY sex reversal."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n FGF9 also contributes to the patterning and differentiation of other organ systems. In limb development, FGF9 is one of several apical ectodermal ridge–derived FGFs that, in a cumulative manner with FGF4 and FGF17, help regulate proximal–distal patterning even though FGF8 can be sufficient on its own."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In the lung, FGF9 is secreted both from the mesothelium and the epithelium, where it drives proliferation in distinct mesenchymal compartments, helps to maintain SHH signaling, represses smooth muscle differentiation, and promotes vascular development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the skin, FGF9 released by γδ T cells is a key mediator of wound‐induced hair neogenesis. It initiates Wnt expression in wound fibroblasts and establishes a positive feedback loop that amplifies Wnt activity during the regenerative process."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n FGF9 also plays notable roles in disease. It can act in a paracrine manner to expand the pool of breast cancer stem–like cells, thereby enhancing tumorigenic potential."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Furthermore, elevated FGF9 expression has been linked to FGFR-dependent signaling in basal-like breast and lung cancers"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and in hepatocellular carcinoma, its overexpression—when not repressed by tumor suppressor miR-140-5p—contributes to proliferation and metastatic behavior."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In prostate cancer, FGF9 overexpression is associated with the promotion of osteoblast proliferation and new bone formation, thereby contributing to osteoblastic metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in organogenesis and neoplasia, FGF9 is critical for maintaining stem and progenitor cell populations. In kidney development, it acts redundantly with FGF20 to preserve the nephron progenitor niche and prevent premature differentiation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ", while in the developing neocortex, FGF9 upregulation is associated with the timely initiation of gliogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n FGF9 further regulates cell fate decisions in germ cells by upregulating NANOS2, thereby acting as an inhibitor of meiotic entry in both male and female primordial germ cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Lastly, during skeletal development, FGF9 is expressed in the vicinity of forming skeletal elements where it promotes early chondrocyte hypertrophy, regulates vascularization of the growth plate, and guides osteogenesis – with FGF9 deficiency leading to rhizomelia, a disproportionate shortening of the proximal skeletal elements."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " In addition, FGF9 functions as a selective ligand for FGFR2c, emphasizing its diverse roles in both normal development and cancer progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yuna Kim, Akio Kobayashi, Ryohei Sekido, et al. 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