{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nFOXL2 is a forkhead transcription factor with a central role in ovarian development and function. Mutations in FOXL2 cause a spectrum of dysgenetic conditions exemplified by blepharophimosis–ptosis–epicanthus inversus syndrome (BPES), which may occur with premature ovarian failure. In BPES, diverse FOXL2 mutations—including missense changes, truncations, and polyalanine expansions—alter the protein’s subcellular localization and transactivation ability, thereby disrupting normal craniofacial and ovarian development. These studies reveal that FOXL2 exerts a dosage‐ and context‐dependent influence on target gene expression, and that even subtle alterations in FOXL2 activity can shift developmental outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn ovarian granulosa cell tumors and other sex cord‐stromal neoplasms, a highly recurrent somatic FOXL2 mutation (c.402C>G, p.C134W) is nearly pathognomonic and underscores FOXL2’s critical oncologic relevance. Functional studies indicate that, in its wild‐type form, FOXL2 triggers apoptotic signals and regulates cell‐cycle mediators in granulosa cells; conversely, the p.C134W mutant shows reduced induction of apoptosis and altered expression of key regulators such as cyclin D2. Immunohistochemical profiling also supports FOXL2 as a sensitive and specific diagnostic biomarker for these tumors. Moreover, FOXL2 has been implicated in other malignancies, where its transactivation by upstream factors (for example, HMGA2) contributes to metastasis and epithelial–mesenchymal transition."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "37"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in development and tumor suppression, FOXL2 regulates the transcription of key ovarian genes by binding to dedicated response elements—either on its own or in cooperation with partners such as SF‐1, Smad3, and other coactivators or repressors. This regulation extends to the modulation of enzymes like aromatase (CYP19A1) and CYP17, as well as regulators of follistatin expression, cell-cycle components, and stress response mediators; modulation that is further fine‐tuned by post‐translational modifications and interactions with factors such as SIRT1. Together, these data underscore FOXL2 as a nodal regulator whose precise activity is critical for ovarian homeostasis and whose disruption may lead not only to developmental syndromes but also to divergent neoplastic processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "38"}]}, {"type": "t", "text": "\n"}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Elfride De Baere, Diane Beysen, Christine Oley, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Aromatase is a direct target of FOXL2: C134W in granulosa cell tumors via a single highly conserved binding site in the ovarian specific promoter."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0014389"}], "href": "https://doi.org/10.1371/journal.pone.0014389"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21188138"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21188138"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Bérénice A Benayoun, Adrien B Georges, David L'Hôte, et al. 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