Affinage

FOXL2

Forkhead box protein L2 · UniProt P58012

Length
376 aa
Mass
38.8 kDa
Annotated
2026-06-09
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FOXL2 is a forkhead transcription factor that acts as a master regulator of ovarian granulosa cell identity and is a bona fide female sex-determining gene, with biallelic loss in goat and tilapia driving XX female-to-male sex reversal (PMID:24485832, PMID:28838139). It establishes and maintains ovarian fate by antagonizing the male SOX9-driven program: genome-wide ChIP-seq shows extensive overlap of FOXL2 occupancy with SOX9 sites, and ectopic FOXL2 represses Sertoli-cell genes (SOX9, DMRT1, AMH) to cause partial testis-to-ovary reprogramming (PMID:30212841, PMID:31505465). FOXL2 directly binds and regulates a panel of gonadal and pituitary target promoters/enhancers, repressing Sf1 by antagonizing WT1-KTS (PMID:24451388), transactivating AMH (PMID:24973035), and cooperating with the activin/TGF-β pathway through direct association with SMAD3 to drive follistatin transcription (PMID:19106105). In pituitary gonadotropes FOXL2 acts together with SMAD4 as an essential, continuously required driver of activin-dependent Fshb/FSH synthesis (PMID:21700720, PMID:24739304, PMID:29800110) and co-regulates the glycoprotein hormone α-subunit gene Cga (PMID:16840539). FOXL2 function depends on an intact forkhead domain for nuclear localization and DNA binding (PMID:18484667), and proper folliculogenesis requires tightly tuned FOXL2 dosage, as overexpression disrupts germ cell nest breakdown, granulosa differentiation, and ovulation (PMID:32945847). Beyond transcription, FOXL2 governs DNA double-strand break repair pathway choice: acetylated FOXL2 sequesters the Ku (XRCC5/XRCC6) complex, and SIRT1-mediated deacetylation at lysine 124 liberates Ku to promote NHEJ over HR (PMID:32332759), and wild-type FOXL2 induces granulosa cell apoptosis via TNF-R1/Fas–caspase 8–BID–BAK–cytochrome c signaling (PMID:21119601). FOXL2 mutation causes blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), with genotype-phenotype correlation to type I (with premature ovarian failure) versus type II [#1-clarify], and the recurrent somatic C134W mutation defines adult-type granulosa cell tumors (PMID:19516027): C134W alters DNA-binding specificity, hijacks SMAD4/SMAD2/3 to a novel hybrid motif driving EMT-related transcription (PMID:32641411, PMID:32641414), abolishes apoptotic signaling (PMID:21119601), and the mutant transcript is selectively degraded by a non-canonical AGO3/DHX9 miRISC triggered by a miR-1236 site created by the mutation, producing FOXL2 haploinsufficiency (PMID:33215742).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    Establishing that FOXL2 loss-of-function underlies a human syndrome combining eyelid and ovarian defects first linked the gene to gonadal and craniofacial development.

    Evidence Direct sequencing and genotype-phenotype correlation across BPES families

    PMID:11468277

    Open questions at the time
    • Did not define FOXL2 molecular targets or mechanism
    • Mechanism linking forkhead-domain truncation to ovarian failure unresolved
  2. 2005 Medium

    Identifying that FOXL2 induces granulosa cell apoptosis and binds the DEAD-box protein DP103 began connecting FOXL2 to cell-fate control in the ovary.

    Evidence Co-IP and overexpression/viability assays in CHO and rat granulosa cells

    PMID:16153597

    Open questions at the time
    • Single Co-IP without reciprocal validation
    • Apoptotic effector pathway not defined here
  3. 2006 High

    Placing FOXL2 upstream of gonadotrope-specific genes in the pituitary extended its role beyond the ovary to endocrine development.

    Evidence Immunofluorescence co-localization, reporter assays, and a FOXL2-VP16 transgenic mouse driving ectopic Cga

    PMID:16840539

    Open questions at the time
    • Direct binding to Cga not demonstrated by ChIP
    • Cofactor requirements for pituitary action not defined
  4. 2008 High

    Demonstrating cooperative FOXL2-Smad3 binding at the follistatin enhancer revealed how FOXL2 integrates activin/TGF-β signaling at target genes.

    Evidence ChIP, reciprocal Co-IP, domain mutagenesis, and luciferase reporters in gonadotrope cells

    PMID:19106105

    Open questions at the time
    • Selectivity for Smad3 over Smad2/Smad4 mechanism unexplained
    • In vivo requirement not tested in this study
  5. 2008 Medium

    Mapping the forkhead domain as essential for nuclear localization clarified why domain-disrupting mutations abolish FOXL2 function.

    Evidence Subcellular localization and transactivation assays of L108P versus S217C variants with structural modeling

    PMID:18484667

    Open questions at the time
    • Single study, limited variant set
    • Does not address DNA-binding specificity determinants
  6. 2009 High

    Discovering the recurrent somatic C134W mutation in nearly all adult-type granulosa cell tumors established FOXL2 as the defining driver of this cancer.

    Evidence Whole-transcriptome RNA sequencing with orthogonal sequencing/RFLP validation across a tumor cohort

    PMID:19516027

    Open questions at the time
    • Functional consequence of C134W not resolved at discovery
    • Tumor-suppressor versus oncogene role of mutant unclear
  7. 2010 Medium

    Defining the wild-type FOXL2 apoptotic cascade and its loss in C134W provided a mechanistic basis for tumorigenesis through apoptosis evasion.

    Evidence Overexpression/knockdown, caspase assays, Western blot, flow cytometry, and death receptor blockade in granulosa cells

    PMID:21119601

    Open questions at the time
    • Single lab
    • Direct transcriptional targets of the death-receptor induction not mapped
  8. 2014 High

    Genetic knockout in goat and tilapia proved FOXL2 is a bona fide female sex-determining gene acting via aromatase induction and male-pathway repression.

    Evidence ZFN biallelic knockout in goat and CRISPR knockout with estradiol rescue in tilapia

    PMID:24485832 PMID:28838139

    Open questions at the time
    • Direct binding to all sex-pathway targets not established
    • Conservation of mechanism to humans inferred, not tested
  9. 2014 Medium

    Showing FOXL2 represses Sf1 and transactivates AMH defined direct transcriptional nodes controlling gonadal somatic differentiation and follicle reserve.

    Evidence ChIP/EMSA, reporter assays with binding-site mutagenesis, and in vivo knockout/knockdown in mice

    PMID:24451388 PMID:24973035

    Open questions at the time
    • Cofactor requirements at these promoters not fully mapped
    • Quantitative contribution to phenotype unresolved
  10. 2014 High

    Conditional double knockout established FOXL2 and SMAD4 as joint, essential in vivo drivers of FSH synthesis, formalizing the activin/SMAD–FOXL2 axis.

    Evidence Cre-lox conditional Smad4/Foxl2 deletion in gonadotropes with hormone and fertility readouts; later confirmed in adult inducible model

    PMID:21700720 PMID:24739304 PMID:29800110

    Open questions at the time
    • Genome-wide FOXL2-SMAD4 cobinding in vivo not mapped here
    • Mechanism of continued adult requirement not detailed
  11. 2018 High

    Genome-wide ChIP-seq revealing FOXL2-SOX9 binding-site overlap mechanistically grounded the FOXL2-SOX9 antagonism that maintains ovarian versus testicular fate.

    Evidence FOXL2 and SOX9 ChIP-seq plus transgenic gain-of-function causing partial sex reversal in mouse

    PMID:30212841 PMID:31505465

    Open questions at the time
    • Whether overlap reflects competition or sequential occupancy unresolved
    • Aromatase activation requires additional factors not identified
  12. 2020 High

    Showing C134W acquires SMAD4/SMAD2/3 binding at a novel hybrid motif explained the gain-of-function transcriptional reprogramming toward EMT in tumors.

    Evidence ChIP-seq and transcriptomics in isogenic inducible lines with SMAD knockdown; two independent studies

    PMID:32641411 PMID:32641414

    Open questions at the time
    • Whether hybrid-motif targets are sufficient for transformation untested
    • Chromatin-remodeling machinery recruited not identified
  13. 2020 High

    Identifying acetylation-dependent FOXL2 sequestration of Ku, reversed by SIRT1 deacetylation at K124, revealed a non-transcriptional role governing DSB repair pathway choice.

    Evidence Reciprocal Co-IP, K124 site mutagenesis, FOXL2 ablation, and DSB repair kinetics with nuclear fractionation

    PMID:32332759

    Open questions at the time
    • Relevance to granulosa tumorigenesis not directly tested
    • Whether C134W alters this function unknown
  14. 2020 Medium

    Demonstrating selective miR-1236/AGO3/DHX9-mediated degradation of the C134W transcript provided a mechanism for FOXL2 haploinsufficiency in tumors.

    Evidence Luciferase target validation, AGO3/DHX9 Co-IP, mouse AGCT model, and patient samples

    PMID:33215742

    Open questions at the time
    • Non-canonical miRISC composition incompletely defined
    • Generality across tumors not established
  15. 2024 High

    Multi-omics mapping of developmental FOXL2 chromatin occupancy and its on-chromatin interactome (including USP7) defined how FOXL2 target repertoire expands postnatally to control folliculogenesis.

    Evidence ChIP-seq/ATAC-seq/RNA-seq, on-chromatin interaction proteomics, and Usp7 conditional deletion in mice

    PMID:38517962

    Open questions at the time
    • Functional roles of most newly identified interactors untested
    • Direct USP7-FOXL2 biochemical relationship not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FOXL2 dosage, post-translational modification, and cofactor switching are integrated to flip between its transcriptional, apoptotic, and DNA-repair roles in a single cell remains unresolved.
  • No unified model linking acetylation state to target selection
  • Structural basis of C134W motif change not solved
  • How normal versus tumor cofactor complexes are partitioned unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4 GO:0140313 molecular sequestering activity 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 1 R-HSA-73894 DNA Repair 1
Partners
AGO3SIRT1SMAD2SMAD3SMAD4USP7XRCC5XRCC6

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 A single recurrent somatic missense mutation in FOXL2 (402C→G; p.C134W) was identified in 97% of adult-type granulosa cell tumors (GCTs) by whole-transcriptome paired-end RNA sequencing, direct sequencing, and restriction-fragment-length polymorphism analysis, implicating mutant FOXL2 as a driver of adult-type GCT pathogenesis. Whole-transcriptome paired-end RNA sequencing, direct sequencing of cDNA and genomic DNA, RFLP analysis, TaqMan assays The New England journal of medicine High 19516027
2001 Mutations in FOXL2 cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); truncating mutations lacking or containing the forkhead domain cause BPES type I (with premature ovarian failure), whereas duplications/frameshifts downstream of the forkhead domain leading to extended protein cause BPES type II, establishing a genotype-phenotype correlation. Direct sequencing of FOXL2 coding region, mutation analysis in BPES families, genotype-phenotype correlation analysis Human molecular genetics High 11468277
2008 FOXL2 binds to a forkhead-binding element (FKHB) immediately downstream of a Smad-binding element (SBE1) in the follistatin gene intronic enhancer, and directly associates with Smad3 (but not Smad2 or Smad4) via Smad3's MH2 domain, requiring an intact forkhead domain in FOXL2, to cooperatively drive activin-induced follistatin transcription in gonadotrope cells. Proteomics approach, chromatin immunoprecipitation, co-immunoprecipitation, shRNA knockdown, luciferase reporter assay The Journal of biological chemistry High 19106105
2010 Wild-type FOXL2 induces apoptosis in granulosa cells via caspase 8 activation, BID cleavage, BAK oligomerization, and cytochrome c release, with upregulation of TNF-R1 and Fas; the C134W mutant FOXL2 fails to elicit this apoptotic signaling cascade, providing a mechanism by which the mutation contributes to GCT development. Overexpression and knockdown experiments, caspase activity assays, Western blotting, flow cytometry, death receptor blockade Oncogene Medium 21119601
2005 FOXL2 induces apoptosis in granulosa cells and interacts with DP103 (a DEAD-box containing protein); co-expression of DP103 with FOXL2 potentiates cell death. Co-immunoprecipitation, overexpression in CHO and rat granulosa cells, cell viability assays Biochemical and biophysical research communications Medium 16153597
2006 FOXL2 co-localizes with the glycoprotein hormone alpha-subunit (αGSU) in essentially all gonadotropes and thyrotropes of the mouse pituitary from embryonic day 11.5 through adulthood, and regulates mouse Cga (αGSU) transcription in a context-dependent manner; a FOXL2-VP16 fusion is sufficient to drive ectopic Cga expression in transgenic animals, placing FOXL2 in the pituitary developmental hierarchy upstream of gonadotrope-specific genes. Immunofluorescence co-localization, luciferase reporter assays in multiple cell lines, transgenic mouse with FOXL2-VP16 fusion Molecular endocrinology (Baltimore, Md.) High 16840539
2011 In Foxl2 mutant mice, FSHβ levels are severely impaired in both sexes, activin fails to drive Fshb expression in pituitary cells from mutants, and FSH secretion is undetectable, establishing that FOXL2 is required in pituitary gonadotropes for normal activin-dependent FSHβ transcription. Foxl2 mutant mouse analysis, primary pituitary cell culture with activin treatment, RIA for FSH, quantitative RT-PCR Molecular endocrinology (Baltimore, Md.) High 21700720
2014 SMAD4 and FOXL2 together are essential master regulators of Fshb transcription in vivo; conditional knockout of Smad4 alone or combined with Foxl2 deletion in gonadotropes abolishes FSH synthesis, and simultaneous deletion causes female sterility phenotypically similar to Fshb knockout mice. Conditional gene targeting (Cre-lox) in mice, hormone measurements, fertility assessment FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 24739304
2018 Deletion of Foxl2 and Smad4 in gonadotropes of adult mice using tamoxifen-inducible Cre causes profound reduction in FSH levels, arrested ovarian follicle development, and sterility, demonstrating that FOXL2 and SMAD4 are required for ongoing FSH synthesis in adult gonadotropes, not just during development. Tamoxifen-inducible conditional knockout (Cre-lox) in adult mice, FSH measurements, ovarian histology, fertility assessment Endocrinology High 29800110
2014 FOXL2 transcriptionally represses Sf1 expression by binding a conserved FOXL2 binding site in the Sf1 proximal promoter and antagonizing WT1-KTS; in Foxl2-null mice, Sf1 expression is increased 2-fold in XX fetal gonads, and mutation of the FOXL2 binding site abolishes repression in reporter assays. Quantitative RT-PCR, luciferase reporter assays, in vitro chromatin immunoprecipitation, Foxl2-null mouse analysis FASEB journal : official publication of the Federation of American Societies for Experimental Biology Medium 24451388
2018 Genome-wide ChIP-seq of FOXL2 in fetal mouse ovaries revealed extensive overlap with SOX9-binding sites in the fetal testis, implying antagonistic FOXL2-SOX9 interactions at the chromatin level; ectopic FOXL2 expression in the fetal testis repressed Sertoli cell differentiation, causing partial testis-to-ovary sex reversal. Genome-wide ChIP-seq (FOXL2 and SOX9), transgenic mouse gain-of-function model, transcriptomic analysis Human molecular genetics High 30212841
2014 FOXL2 is a female sex-determining gene in the goat: zinc-finger nuclease-directed biallelic knockout of FOXL2 alone (dissociated from lncRNA loss) causes XX female-to-male sex reversal and eyelid agenesis, establishing FOXL2 as a bona fide female sex-determining gene. Zinc-finger nuclease-directed mutagenesis, cloning from XX FOXL2-/- fibroblasts, histological and molecular phenotypic analysis Current biology : CB High 24485832
2017 In Nile tilapia, foxl2-/- XX fish display female-to-male sex reversal with downregulation of Cyp19a1a and estradiol, upregulation of Sf1/Dmrt1/Gsdf and androgen production; foxl2-/- phenotype is rescued by 17β-estradiol treatment; Foxl2 suppresses star1 transcription in a dose-dependent manner in vitro, demonstrating that FOXL2 promotes ovarian development by upregulating aromatase and repressing male pathway genes. CRISPR/Cas9 knockout, 17β-estradiol rescue experiment, in vitro promoter analysis, hormone measurement Endocrinology High 28838139
2020 FOXL2 C134W mutant acquires the ability to bind SMAD4, forming a FOXL2C134W/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif (AGHCAHAA) unique to the mutant, inducing an enhancer-like chromatin state and transcription of genes characteristic of epithelial-to-mesenchymal transition; ablation of SMAD4 or SMAD2/3 strongly reduces FOXL2C134W binding at hybrid sites. ChIP-seq, transcriptome profiling, Co-immunoprecipitation, SMAD4/SMAD2/3 knockdown, isogenic inducible cell lines Cancer research High 32641411
2020 FOXL2 C134W mutation alters DNA-binding specificity of FOXL2: ChIP-seq in V5-FOXL2C134W isogenic inducible cell lines showed that the mutant associates with a large collection of unique genomic elements in addition to the majority of wild-type sites, altering the transcriptional program including upregulation of SLC35F2. ChIP-seq, transcriptome profiling, engineered isogenic inducible cell lines (V5-FOXL2WT and V5-FOXL2C134W) Cancer research High 32641414
2020 Upon DNA double-strand break (DSB) induction, SIRT1 translocates to the nucleus and deacetylates FOXL2 at lysine 124, causing liberation of XRCC5 and XRCC6 (Ku complex) from FOXL2; acetylated FOXL2 sequesters Ku, and FOXL2 ablation enhances Ku recruitment to DSB sites, accelerating NHEJ and inhibiting HR, demonstrating that FOXL2 governs DSB repair pathway choice through an acetylation-dependent interaction with the Ku complex. Co-immunoprecipitation, site-specific mutagenesis (K124 acetylation), FOXL2 ablation, DSB repair kinetics assays, nuclear fractionation Nature communications High 32332759
2020 The somatic heterozygous FOXL2 c.402C>G mutation introduces a target site for miR-1236 within the FOXL2 coding sequence; a non-canonical miRISC directed by AGO3 and DHX9 preferentially degrades the variant FOXL2 mRNA, causing haploinsufficiency of the tumor-suppressor FOXL2 in adult-type GCTs. miRNA target site validation (luciferase assay), AGO3/DHX9 co-immunoprecipitation, mouse AGCT model, patient samples The EMBO journal Medium 33215742
2013 Wild-type FOXL2 (but not C134W mutant) induces follistatin production in granulosa tumor cells; overexpression of wild-type FOXL2 attenuates activin A-stimulated cell proliferation via follistatin, establishing a tumor-suppressor mechanism for wild-type FOXL2 in GCTs. Overexpression of WT and C134W mutant FOXL2, exogenous follistatin treatment, cell proliferation assays, luciferase reporter Biochemical and biophysical research communications Medium 24332943
2014 FOXL2 transactivates the AMH gene promoter (confirmed by luciferase reporter assay, EMSA, and ChIP); BPES-associated mutant FOXL2 proteins are defective in AMH transactivation; in vivo, Amh knockdown accelerates follicle growth and FOXL2 overexpression prevents this acceleration, demonstrating positive cross-talk between FOXL2 and AMH in ovarian follicle reserve maintenance. Luciferase reporter assay, EMSA, chromatin immunoprecipitation, in vivo nucleic acid delivery in mice, ovarian histology Fertility and sterility Medium 24973035
2012 Mutant FOXL2 differentially regulates transcription of StAR and CYP19A (known FOXL2 targets) and a suite of TGF-β signaling genes compared to wild-type FOXL2, as identified by microarray analysis in GCT cell lines following overexpression and knockdown, suggesting deregulation of anti-proliferative TGF-β signaling in GCT pathogenesis. siRNA knockdown and overexpression in GCT cell lines (KGN, COV434), Affymetrix microarray, permutation analysis PloS one Low 23029457
2017 FOXL2 transactivation in chemoresistant gastric cancer is driven by interaction between HMGA2 and pRb facilitating E2F1-mediated FOXL2 transcription; FOXL2 then acts downstream of HMGA2 to regulate ITGA2 expression and promote metastasis and EMT. Co-immunoprecipitation, luciferase reporter assays, loss-of-function and gain-of-function in vitro and in vivo (orthotopic mouse model) Clinical cancer research : an official journal of the American Association for Cancer Research Medium 28119367
2015 Conditional deletion of Foxl2 in the postnatal uterus (using Pgr-Cre) causes infertility with reduced stromal layer thickness, hypertrophic inner myometrial layer, supplementary muscular layer formation, and failure of vascular smooth muscle organization; Wnt signaling genes are deregulated in Foxl2-deleted uteri, suggesting FOXL2 acts through Wnt signals in uterine maturation. Conditional knockout (Pgr-Cre; Foxl2-flox), histological analysis, gene expression analysis Human molecular genetics Medium 25687138
2024 Multi-omics analysis of FOXL2 chromatin occupancy in ovarian somatic cells across development revealed that FOXL2 regulates more targets postnatally through interaction with factors regulating primordial follicle formation and steroidogenesis; deletion of FOXL2 interactor USP7 impairs somatic cell differentiation, germ cell nest breakdown, and ovarian development leading to sterility. Multi-omics (ChIP-seq, ATAC-seq, RNA-seq), genome-wide FOXL2 target identification, on-chromatin interaction proteomics, Usp7 conditional deletion in mice Science advances High 38517962
2012 FOXL2 directly stimulates the clusterin (Clu) gene promoter in pituitary gonadotroph cells, and FOXL2 also binds and suppresses the PTTG promoter; FOXL2 and clusterin together restrain pituitary cell proliferation via induction of CDK inhibitors p16 and p27. Promoter-reporter (luciferase) assays, xenograft tumor growth assay with FOXL2/Clu overexpression Molecular endocrinology (Baltimore, Md.) Low 23051594
2008 The missense mutation p.Leu108Pro in the forkhead domain of FOXL2 causes strong cytoplasmic mislocalization of the protein and loss of transcriptional activity, while p.Ser217Cys (between forkhead and polyalanine domains) shows normal localization and transactivation, demonstrating that the forkhead domain is required for nuclear localization and transcriptional function. Subcellular localization assays (fluorescence microscopy), transcriptional activity reporter assays, structural modeling of forkhead domain Human mutation Medium 18484667
2019 In embryonic chicken gonads, FOXL2 overexpression in XY gonads suppresses SOX9, DMRT1, and AMH expression and represses Sertoli cell development; conversely, FOXL2 knockdown in female gonads allows ectopic SOX9 activation, establishing FOXL2 as an embryonic antagonist of the male SOX9-driven pathway. FOXL2 misexpression alone was insufficient to activate aromatase in male gonads. In ovo overexpression and knockdown (electroporation/RNAi), immunofluorescence, qRT-PCR The Journal of endocrinology Medium 31505465
2023 Phosphorylated ERK1/2 down-regulates FOXL2 expression and up-regulates SOX9 in granulosa cells; SOX9 is found to regulate FOXL2 as well as CYP19A1 and STAR in granulosa cells, suggesting an ERK1/2-SOX9/FOXL2 axis that controls the switch from estradiol to progesterone production during follicular-luteal transition. ERK inhibition/activation in cultured granulosa cells, Western blotting, qRT-PCR, siRNA knockdown of SOX9 Life science alliance Low 37532283
2015 Foxl2-null mice show defects in postnatal growth, skeletal abnormalities, and defects in cartilage and bone mineralization, with down-regulation of the GH/IGF1 axis; FOXL2 is expressed in embryonic cartilaginous tissue and hypothalamus, overlapping with SOX9 expression in cartilage. Foxl2 knockout mouse analysis, skeletal staining (alcian blue/alizarin red/Von Kossa), immunofluorescence, microarray, RT-qPCR of GH/IGF1 axis markers BMC developmental biology Medium 26134413
2015 FOXL2 interacts with FTZ-F1 (via the forkhead domain of FOXL2, as identified by co-immunoprecipitation), and with DDX20; FOXL2 down-regulates vitellogenin expression in Eriocheir sinensis at the mature ovarian stage by binding DDX20 to regulate follicular cell apoptosis and by interacting with FTZ-F1 to repress VTG synthesis. Co-immunoprecipitation, domain interaction mapping, immunofluorescence, expression knockdown Bioscience reports Low 26430246
2020 Aberrant constitutive overexpression of FOXL2 in ovarian somatic cells impairs germ cell nest breakdown, causes polyovular follicle formation, impairs granulosa cell differentiation, compromises theca cell recruitment and steroidogenesis, and prevents ovulation, demonstrating that fine-tuned FOXL2 expression level is required for folliculogenesis. Transgenic FOXL2 overexpression mouse model, ovarian histology, steroidogenesis measurements, immunofluorescence Biology of reproduction Medium 32945847

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mutation of FOXL2 in granulosa-cell tumors of the ovary. The New England journal of medicine 608 19516027
2001 Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation. Human molecular genetics 214 11468277
2010 The FOXL2 C134W mutation is characteristic of adult granulosa cell tumors of the ovary. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 189 20693978
2003 FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. American journal of human genetics 187 12529855
2011 FOXL2 is a sensitive and specific marker for sex cord-stromal tumors of the ovary. The American journal of surgical pathology 149 21378549
2014 FOXL2 is a female sex-determining gene in the goat. Current biology : CB 140 24485832
2017 Mutation of foxl2 or cyp19a1a Results in Female to Male Sex Reversal in XX Nile Tilapia. Endocrinology 133 28838139
2017 HMGA2-FOXL2 Axis Regulates Metastases and Epithelial-to-Mesenchymal Transition of Chemoresistant Gastric Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 131 28119367
2013 FOXL2: a central transcription factor of the ovary. Journal of molecular endocrinology 131 24049064
2006 Molecular cloning and analysis of gonadal expression of Foxl2 in the medaka, Oryzias latipes. Biochemical and biophysical research communications 126 16630569
2006 FOXL2 in the pituitary: molecular, genetic, and developmental analysis. Molecular endocrinology (Baltimore, Md.) 116 16840539
2003 Structure, evolution and expression of the FOXL2 transcription unit. Cytogenetic and genome research 108 14684984
2006 Foxl2 function in ovarian development. Molecular genetics and metabolism 106 16647286
2009 FOXL2 mutations and genomic rearrangements in BPES. Human mutation 98 18726931
2008 FOXL2 and SOX9 as parameters of female and male gonadal differentiation in patients with various forms of disorders of sex development (DSD). The Journal of pathology 98 18348162
2008 FoxL2 and Smad3 coordinately regulate follistatin gene transcription. The Journal of biological chemistry 95 19106105
2010 Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W). Oncogene 88 21119601
2015 DICER1 and FOXL2 mutations in ovarian sex cord-stromal tumours: a GINECO Group study. Histopathology 86 26033501
2011 Minireview: roles of the forkhead transcription factor FOXL2 in granulosa cell biology and pathology. Endocrinology 86 21248146
2016 Foxl2 and Its Relatives Are Evolutionary Conserved Players in Gonadal Sex Differentiation. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 84 27441599
2017 Sex determination and maintenance: the role of DMRT1 and FOXL2. Asian journal of andrology 76 28091399
2019 DICER1 and FOXL2 Mutation Status Correlates With Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors. The American journal of surgical pathology 73 30986800
2014 Follicle-stimulating hormone synthesis and fertility depend on SMAD4 and FOXL2. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 70 24739304
2010 FOXL2 versus SOX9: a lifelong "battle of the sexes". BioEssays : news and reviews in molecular, cellular and developmental biology 68 20414895
2011 The transcription factor FOXL2: at the crossroads of ovarian physiology and pathology. Molecular and cellular endocrinology 67 21763750
2013 FOXL2 molecular testing in ovarian neoplasms: diagnostic approach and procedural guidelines. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 65 23348906
2012 The transcriptional targets of mutant FOXL2 in granulosa cell tumours. PloS one 64 23029457
2007 Extinction of FOXL2 expression in aggressive ovarian granulosa cell tumors in children. Fertility and sterility 60 17430735
2005 Transcriptional factor FOXL2 interacts with DP103 and induces apoptosis. Biochemical and biophysical research communications 58 16153597
2012 WNT4, RSPO1, and FOXL2 in sex development. Seminars in reproductive medicine 55 23044875
2007 The mutations and potential targets of the forkhead transcription factor FOXL2. Molecular and cellular endocrinology 55 18155828
2016 Involvement of FOXL2 and RSPO1 in Ovarian Determination, Development, and Maintenance in Mammals. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 51 27649556
2016 Impact of FOXL2 mutations on signaling in ovarian granulosa cell tumors. The international journal of biochemistry & cell biology 50 26791928
2018 Genome-wide identification of FOXL2 binding and characterization of FOXL2 feminizing action in the fetal gonads. Human molecular genetics 49 30212841
2016 WNT/β-catenin and p27/FOXL2 differentially regulate supporting cell proliferation in the developing ovary. Developmental biology 48 26939755
2009 Adult-type granulosa cell tumors and FOXL2 mutation. Cancer research 48 19996294
2004 The human FOXL2 mutation database. Human mutation 47 15300845
2020 Mutant FOXL2C134W Hijacks SMAD4 and SMAD2/3 to Drive Adult Granulosa Cell Tumors. Cancer research 46 32641411
2005 Foxl2 gene and the development of the ovary: a story about goat, mouse, fish and woman. Reproduction, nutrition, development 46 15982462
2009 FOXL2 mutations lead to different ovarian phenotypes in BPES patients: Case Report. Human reproduction (Oxford, England) 45 19819892
2018 FOXL2 and DMRT1L Are Yin and Yang Genes for Determining Timing of Sex Differentiation in the Bivalve Mollusk Patinopecten yessoensis. Frontiers in physiology 44 30246781
2021 Functional Divergence of Multiple Duplicated Foxl2 Homeologs and Alleles in a Recurrent Polyploid Fish. Molecular biology and evolution 43 33432361
2016 The genetic make-up of ovarian development and function: the focus on the transcription factor FOXL2. Clinical genetics 42 27604691
2014 FOXL2 transcriptionally represses Sf1 expression by antagonizing WT1 during ovarian development in mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 42 24451388
2019 Adult Granulosa Cell Tumor With High-grade Transformation: Report of a Series With FOXL2 Mutation Analysis. The American journal of surgical pathology 39 31162286
2012 FOXL2 impairment in human disease. Hormone research in paediatrics 39 22248822
2003 Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients. Human mutation 39 12938087
2014 Molecular cloning and analysis of gonadal expression of Foxl2 in the rice-field eel Monopterus albus. Scientific reports 37 25363394
1993 Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) associated with interstitial deletion of band 3q22: review and gene assignment to the interface of band 3q22.3 and 3q23. American journal of medical genetics 37 8291545
2017 Testis Determination Requires a Specific FGFR2 Isoform to Repress FOXL2. Endocrinology 36 28938467
2021 Adult-type granulosa cell tumor of the ovary: a FOXL2-centric disease. The journal of pathology. Clinical research 35 33428330
2014 Positive cross talk between FOXL2 and antimüllerian hormone regulates ovarian reserve. Fertility and sterility 35 24973035
2011 Cloning and differential expression of FOXL2 during ovarian development and recrudescence of the catfish, Clarias gariepinus. General and comparative endocrinology 35 21906596
2019 FOXL2 antagonises the male developmental pathway in embryonic chicken gonads. The Journal of endocrinology 34 31505465
2011 Impaired FSHbeta expression in the pituitaries of Foxl2 mutant animals. Molecular endocrinology (Baltimore, Md.) 33 21700720
2020 FOXL2 directs DNA double-strand break repair pathways by differentially interacting with Ku. Nature communications 32 32332759
2015 Role of Foxl2 in uterine maturation and function. Human molecular genetics 32 25687138
2014 MiR-30a upregulates BCL2A1, IER3 and cyclin D2 expression by targeting FOXL2. Oncology letters 32 25621074
2021 The Genetics and Biology of FOXL2. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 30 34727551
2009 Gonadal sex differentiation and expression of Sox9a2, Dmrt1, and Foxl2 in Oryzias luzonensis. Genesis (New York, N.Y. : 2000) 30 19298014
2005 Sense and antisense Foxl2 transcripts in mouse. Genomics 30 15820304
2013 The role of FOXL2 in the pathogenesis of adult ovarian granulosa cell tumours. Gynecologic oncology 29 24342437
2005 Interstitial deletion in 3q in a patient with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and microcephaly, mild mental retardation and growth delay: clinical report and review of the literature. American journal of medical genetics. Part A 29 16015581
2018 FOXL2 Mutation Analysis of Ovarian Sex Cord-Stromal Tumors: Genotype-Phenotype Correlation With Diagnostic Considerations. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 28 28700438
2002 Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families. American journal of medical genetics 28 12400065
1996 Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). Acta ophthalmologica Scandinavica 28 8689480
2018 Conditional Deletion of FOXL2 and SMAD4 in Gonadotropes of Adult Mice Causes Isolated FSH Deficiency. Endocrinology 27 29800110
2015 microRNA133a targets Foxl2 and promotes differentiation of C2C12 into myogenic progenitor cells. DNA and cell biology 27 25317675
2013 Adult granulosa cell tumours (GCT): clinicopathological outcomes including FOXL2 mutational status and expression. Gynecologic oncology 27 24007948
2012 Clusterin and FOXL2 act concordantly to regulate pituitary gonadotroph adenoma growth. Molecular endocrinology (Baltimore, Md.) 26 23051594
2022 Dissecting the fate of Foxl2-expressing cells in fetal ovary using lineage tracing and single-cell transcriptomics. Cell discovery 25 36575161
2017 FOXL2 Mutation Status in Granulosa Theca Cell Tumors of the Ovary. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 25 28319575
2015 FOXL2 down-regulates vitellogenin expression at mature stage in Eriocheir sinensis. Bioscience reports 25 26430246
2021 Rare DICER1 and Absent FOXL2 Mutations Characterize Ovarian Juvenile Granulosa Cell Tumors. The American journal of surgical pathology 23 32910017
2020 The Pathognomonic FOXL2 C134W Mutation Alters DNA-Binding Specificity. Cancer research 23 32641414
2020 Ovarian granulosa cell tumor characterization identifies FOXL2 as an immunotherapeutic target. JCI insight 23 32814714
2020 An alternative miRISC targets a cancer-associated coding sequence mutation in FOXL2. The EMBO journal 23 33215742
2014 FOXL2 in human endometrium: hyperexpressed in endometriosis. Reproductive sciences (Thousand Oaks, Calif.) 23 24520083
2013 FOXL2-induced follistatin attenuates activin A-stimulated cell proliferation in human granulosa cell tumors. Biochemical and biophysical research communications 23 24332943
2008 Differential functional effects of novel mutations of the transcription factor FOXL2 in BPES patients. Human mutation 23 18484667
2023 ERK1/2-SOX9/FOXL2 axis regulates ovarian steroidogenesis and favors the follicular-luteal transition. Life science alliance 22 37532283
2021 Characterization of the foxl2 gene involved in the vtg expression in mud crab (Scylla paramamosain). Gene 22 34224832
2015 FOXL2 modulates cartilage, skeletal development and IGF1-dependent growth in mice. BMC developmental biology 22 26134413
2011 FOXL2 mutation and large-scale genomic imbalances in adult granulosa cell tumors of the ovary. Cancer genetics 22 22200085
2009 The forkhead factor FOXL2: a novel tumor suppressor? Biochimica et biophysica acta 22 19747961
2009 FOXL2: at the crossroads of female sex determination and ovarian function. Advances in experimental medicine and biology 22 20429427
1993 Blepharophimosis sequence (BPES) and microcephaly in a girl with del(3) (q22.2q23): a putative gene responsible for microcephaly close to the BPES gene? American journal of medical genetics 22 8256811
2024 FOXL2 interaction with different binding partners regulates the dynamics of ovarian development. Science advances 21 38517962
2020 Aberrant and constitutive expression of FOXL2 impairs ovarian development and functions in mice. Biology of reproduction 21 32945847
2015 FOXL2 mutation is absent in uterine tumors resembling ovarian sex cord tumors. The American journal of surgical pathology 21 25581731
2014 FOXL2 suppresses proliferation, invasion and promotes apoptosis of cervical cancer cells. International journal of clinical and experimental pathology 21 24817949
2011 Mutation spectrum of fork-head transcriptional factor gene (FOXL2) in Indian Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES) patients. The British journal of ophthalmology 21 21325395
2011 Expression of FOXL2 in human normal pituitaries and pituitary adenomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 21 21478824
2011 FOXL2 C402G mutation detection using MALDI-TOF-MS in DNA extracted from Israeli granulosa cell tumors. Gynecologic oncology 21 21640373
2021 FOXL2 and TERT promoter mutation detection in circulating tumor DNA of adult granulosa cell tumors as biomarker for disease monitoring. Gynecologic oncology 20 34083028
2014 Characterization and gonadal expression of FOXL2 relative to Cyp19a genes in spotted scat Scatophagus argus. Gene 20 25550048
2004 Genetic analysis of a five generation Indian family with BPES: a novel missense mutation (p.Y215C). Molecular vision 20 15257268
2017 MicroRNA-937 inhibits cell proliferation and metastasis in gastric cancer cells by downregulating FOXL2. Cancer biomarkers : section A of Disease markers 19 29060929
2016 Lack of mutation of DICER1 and FOXL2 genes in microcystic stromal tumor of the ovary. Virchows Archiv : an international journal of pathology 18 27830327
2021 The Genetic and Clinical Features of FOXL2-Related Blepharophimosis, Ptosis and Epicanthus Inversus Syndrome. Genes 17 33806295

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