Affinage

FOXL2

Forkhead box protein L2 · UniProt P58012

Length
376 aa
Mass
38.8 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FOXL2 is a forkhead-domain transcription factor that serves as a master regulator of female gonadal identity, granulosa cell differentiation, and pituitary FSH synthesis. In the ovary, FOXL2 maintains female fate by directly repressing testis-determining genes (Sox9, Sf1) and activating ovarian targets (AMH, follistatin, ESR2, aromatase) through cooperative DNA binding with SMAD2/3, SMAD4, SF-1, progesterone receptor, and RUNX1 at adjacent forkhead and SMAD binding elements; loss of FOXL2 causes granulosa cell differentiation failure and, together with loss of Wnt4 or RUNX1, leads to female-to-male sex reversal (PMID:14736745, PMID:17728319, PMID:31712577, PMID:25369636, PMID:24451388). In pituitary gonadotropes, FOXL2 and SMAD4 are jointly essential for activin-stimulated Fshb transcription and FSH secretion, as conditional deletion of either or both abolishes FSH synthesis and causes infertility (PMID:23340250, PMID:24739304, PMID:29800110). The somatic C134W mutation, which is pathognomonic of adult-type granulosa cell tumors, alters FOXL2 DNA-binding specificity genome-wide and enables formation of a neomorphic FOXL2-SMAD4-SMAD2/3 complex that activates an oncogenic transcriptional program, while also creating a coding-sequence target for miR-1236-mediated selective degradation of the mutant allele via AGO3/DHX9, producing tumor-suppressor haploinsufficiency (PMID:32641411, PMID:32641414, PMID:33215742).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2004 High

    Establishing FOXL2 as essential for granulosa cell differentiation answered whether this transcription factor was required for ovary formation and folliculogenesis.

    Evidence Foxl2-lacZ homozygous knockout mice showing absence of secondary follicles, loss of squamous-to-cuboidal transition, and loss of AMH/activin-βA expression

    PMID:14736745

    Open questions at the time
    • Downstream direct transcriptional targets not yet mapped genome-wide
    • Whether FOXL2 functions cell-autonomously in granulosa cells vs. through paracrine effects not resolved
  2. 2005 Medium

    Identification of DP103 as a FOXL2 interactor and demonstration of FOXL2-induced apoptosis suggested a pro-apoptotic function beyond transcriptional regulation of differentiation.

    Evidence Co-IP of FOXL2-DP103 and cell viability assays in CHO and rat granulosa cells

    PMID:16153597

    Open questions at the time
    • Not independently replicated
    • Physiological relevance of DP103 interaction in vivo unknown
    • Mechanism of FOXL2-induced apoptosis not delineated
  3. 2006 High

    Demonstrating FOXL2 expression and function in pituitary gonadotropes expanded its role beyond the ovary to neuroendocrine regulation of reproduction.

    Evidence Immunofluorescence co-localization with αGSU, reporter assays in gonadotrope cell lines, transgenic FOXL2-VP16 driving ectopic Cga expression

    PMID:16840539

    Open questions at the time
    • Direct DNA-binding sites on Cga not mapped
    • Relationship to FSH regulation not yet established
  4. 2007 High

    Genetic epistasis showing that combined Wnt4/Foxl2 loss causes complete female-to-male sex reversal, and that forced FOXL2 impairs testis formation, established FOXL2 as a bona fide anti-testis factor.

    Evidence Double knockout and transgenic overexpression mouse genetics with histological analysis

    PMID:17728319

    Open questions at the time
    • Molecular targets through which FOXL2 antagonizes testis fate not yet identified at chromatin level
    • Whether FOXL2 and Wnt4 converge on common downstream effectors unknown
  5. 2009 High

    Identifying FOXL2 as a SMAD3 partner on the follistatin gene intron revealed the mechanistic basis for FOXL2's integration into TGF-β/activin signaling.

    Evidence Reciprocal co-IP, domain mapping, ChIP, and shRNA knockdown in gonadotrope cells

    PMID:19106105

    Open questions at the time
    • Whether FOXL2-SMAD3 interaction extends genome-wide to other activin targets not determined
    • SMAD4 role in this specific complex unclear
  6. 2010 High

    Discovery that FOXL2 physically interacts with SF-1 to repress CYP17 transcription established a mechanism for maintaining granulosa (vs. theca/Leydig) steroidogenic identity.

    Evidence Yeast two-hybrid, co-IP in human granulosa cells, ChIP, EMSA, and BPES mutant loss-of-function

    PMID:20207836

    Open questions at the time
    • Other SF-1 target genes co-regulated by FOXL2 not systematically identified
    • In vivo validation by conditional KO of FOXL2-SF1 interaction not performed
  7. 2011 High

    Demonstrating that FOXL2 promotes G1 arrest, oxidative stress protection, and DNA repair — modulated by SIRT1 deacetylation — revealed cell-protective functions beyond transcriptional sex determination.

    Evidence FACS cell-cycle analysis, oxidative stress assays, deacetylase inhibitor treatment, BPES mutation-class comparison

    PMID:21289058

    Open questions at the time
    • Specific acetylation sites on FOXL2 targeted by SIRT1 not mapped
    • In vivo relevance of SIRT1-FOXL2 axis in ovary not tested
  8. 2011 High

    Showing that Foxl2-mutant pituitaries fail to produce FSH upon activin stimulation, and that FOXL2 cooperates with SMADs at adjacent Fshb promoter elements, established FOXL2 as the first gonadotrope-specific transcription factor required for FSH synthesis.

    Evidence Foxl2 mutant mouse pituitaries, primary pituitary cultures, reporter assays with promoter mutagenesis

    PMID:21622537 PMID:21700720

    Open questions at the time
    • Whether FOXL2 is sufficient to confer Fshb expression on non-gonadotrope cells unknown
    • Chromatin-level occupancy at endogenous Fshb locus not shown
  9. 2014 High

    A series of conditional knockout and target-gene studies collectively defined FOXL2's direct transcriptional targets (AMH, ESR2, Sf1, Sox9) and the feed-forward logic by which it maintains ovarian identity: FOXL2 activates ESR2, which cooperatively represses Sox9, while FOXL2 directly represses Sf1 by antagonizing WT1.

    Evidence ChIP-seq in primary follicular cells, conditional gonadotrope KOs, reporter assays, EMSA, in vivo gene delivery, double conditional KOs with SMAD4

    PMID:23340250 PMID:24451388 PMID:24739304 PMID:24973035 PMID:25369636

    Open questions at the time
    • Full enhancer-level regulatory network connecting FOXL2 to all ovarian identity genes not mapped
    • How FOXL2 target selection differs between fetal and adult ovary not resolved
  10. 2014 High

    Elucidation of the GSK3β → S33 phosphorylation → MDM2 ubiquitination cascade for C134W FOXL2 degradation vs. SUMOylation-mediated stabilization of wild-type FOXL2 provided a post-translational mechanism for how the oncogenic mutant is differentially regulated.

    Evidence In vitro kinase assays, ubiquitination/SUMOylation assays, mutagenesis, xenograft model, patient tissue analysis

    PMID:24390485

    Open questions at the time
    • Whether other kinases phosphorylate S33 in vivo
    • How SUMOylation modulates wild-type FOXL2 transcriptional activity not detailed
  11. 2015 High

    Conditional uterine deletion revealed FOXL2 functions beyond the ovary and pituitary, being required for uterine stromal and myometrial maturation and Wnt pathway regulation.

    Evidence Pgr-cre conditional KO with histology and expression profiling

    PMID:25687138

    Open questions at the time
    • Direct FOXL2 binding sites in uterine cells not mapped
    • Whether uterine defects contribute to infertility independently of ovarian failure not distinguished
  12. 2018 High

    Genome-wide ChIP-seq in fetal ovary showing FOXL2 occupancy extensively overlapping SOX9 sites, combined with gain-of-function feminization of fetal testis, demonstrated that FOXL2 and SOX9 compete at shared regulatory elements to determine gonadal fate.

    Evidence ChIP-seq in fetal ovary, ectopic FOXL2 transgenic testis model, transcriptomics

    PMID:30212841

    Open questions at the time
    • Whether FOXL2 and SOX9 physically compete for DNA occupancy or act through chromatin remodeling intermediaries not distinguished
  13. 2019 High

    Discovery that RUNX1 acts redundantly with FOXL2 to maintain fetal granulosa identity — with overlapping chromatin occupancy — revealed that ovarian fate maintenance relies on a transcription factor network rather than FOXL2 alone.

    Evidence Double conditional KO causing fetal ovary masculinization, ChIP-seq overlap, single-cell transcriptomics

    PMID:31712577

    Open questions at the time
    • Whether FOXL2 and RUNX1 form a physical complex or act independently at shared sites unknown
    • Other transcription factors in the network not identified
  14. 2020 High

    Mechanistic dissection of the C134W mutation showed it acquires neomorphic DNA-binding specificity, forms a novel complex with SMAD4/SMAD2/3 at hybrid motifs to activate an EMT-associated oncogenic program, while simultaneously being selectively degraded by a miR-1236/AGO3/DHX9 non-canonical miRISC to cause haploinsufficiency — together explaining both gain- and loss-of-function oncogenic mechanisms.

    Evidence ChIP-seq in isogenic WT vs. C134W lines and primary AGCT, CRISPR ablation of SMADs, co-IP, miRNA mutagenesis, AGO3/DHX9 co-IP, mouse AGCT model

    PMID:32641411 PMID:32641414 PMID:33215742

    Open questions at the time
    • Whether pharmacological disruption of the FOXL2C134W-SMAD4 complex is therapeutically viable not tested
    • How miR-1236 expression is regulated in AGCT unknown
    • Structural basis of altered C134W DNA-binding specificity not resolved
  15. 2022 High

    Lineage tracing of FOXL2-expressing cells revealed they are multipotent progenitors giving rise to granulosa, theca-interstitial, and stromal lineages, redefining FOXL2 from a granulosa-specific factor to a marker of a common ovarian somatic progenitor.

    Evidence Cre/Rosa lineage tracing and single-cell RNA-seq across developmental time points

    PMID:36575161

    Open questions at the time
    • Whether FOXL2 is functionally required in theca and stromal differentiation or merely expressed
    • Signals that direct FOXL2+ progenitors toward different lineages not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for C134W neomorphic DNA binding, the full enhancer-level logic by which FOXL2 coordinates with RUNX1 and other factors across ovarian cell types, and whether targeting the FOXL2C134W-SMAD4 axis is therapeutically tractable in granulosa cell tumors.
  • No crystal structure of FOXL2 forkhead domain bound to DNA
  • Therapeutic targeting of FOXL2C134W-SMAD axis untested
  • Single-cell-resolved FOXL2 function across all ovarian somatic lineages incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 12 GO:0003677 DNA binding 7
Localization
GO:0005634 nucleus 7
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-1474165 Reproduction 4 R-HSA-162582 Signal Transduction 4
Partners
ESR1NR5A1PGRRUNX1SIRT1SMAD2SMAD3SMAD4
Complex memberships
FOXL2-SF-1 complexFOXL2-SMAD3 transcriptional complexFOXL2-SMAD4-SMAD2/3 complex (C134W-specific)

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Murine Foxl2 is required for granulosa cell differentiation (squamous-to-cuboidal transition) and ovary maintenance; loss of Foxl2 leads to absence of secondary follicles, oocyte atresia, and loss of activin-betaA and AMH expression, while causing premature activation of primordial follicles Foxl2(lacZ) homozygous knockout mouse model with histological analysis, gene expression studies Development High 14736745
2007 Combined inactivation of Wnt4 and Foxl2 in XX mice produces full female-to-male sex reversal including testis tubule formation and spermatogonia; forced expression of Foxl2 impairs testis tubule differentiation in XY transgenic mice, demonstrating an anti-testis role for Foxl2 Double knockout mouse genetics, transgenic overexpression, histological analysis Human molecular genetics High 17728319
2004 Polyalanine expansion mutations in FOXL2 (14 to 24 alanines) cause extensive intranuclear aggregation and cytoplasmic mislocalisation of the protein; wild-type and mutant proteins can co-aggregate, suggesting a dominant-negative mechanism via sequestration Transfection of GFP-fusion constructs in COS-7 cells, immunofluorescence Journal of medical genetics Medium 15591279
2006 FOXL2 is expressed in pituitary gonadotropes and thyrotropes co-localizing with the glycoprotein hormone alpha-subunit (αGSU/Cga); FOXL2 regulates Cga transcription in gonadotrope-derived cells in a context-dependent manner, and a FOXL2-VP16 fusion drives ectopic Cga expression in transgenic animals; FOXL2 expression requires Lhx3 and Lhx4 Immunofluorescence co-localization, reporter assays in multiple cell lines, transgenic mice, epistasis analysis Molecular endocrinology High 16840539
2008 FoxL2 binds a forkhead-binding element (FKHB) adjacent to a Smad-binding element (SBE1) in the follistatin gene intron, directly associates with Smad3 (but not Smad2 or Smad4) via Smad3's MH2 domain in an interaction requiring an intact FoxL2 forkhead domain, and functions as a Smad3 partner to drive SBE1-mediated follistatin transcription in activin-treated gonadotrope cells Proteomics/co-IP identification, reporter assays, ChIP, shRNA knockdown, domain-mapping co-IP Journal of biological chemistry High 19106105
2010 FOXL2 physically interacts with steroidogenic factor-1 (SF-1) in granulosa cells (identified by yeast two-hybrid and confirmed by co-IP), and represses SF-1-induced CYP17 transcription by inhibiting SF-1 binding to the CYP17 promoter; BPES-associated FOXL2 mutants lose this repressive activity Yeast two-hybrid screen, co-IP in human granulosa cells, ChIP, EMSA, reporter assays, BPES mutant analysis Molecular endocrinology High 20207836
2010 The FOXL2 p.C134W (c.402C>G) tumor-associated mutation does not strongly alter subcellular localization, solubility, or transactivation on most target promoters compared to wild-type, but does exhibit altered activity on an artificial promoter co-regulated by FOXL2 and Smad3, suggesting a subtle modification of FOXL2–Smad3 interaction; 3D structural modeling indicates homodimer formation may be disturbed Subcellular localization studies, transactivation assays on multiple promoters, FRAP, 3D structural modeling PLoS one Medium 20098707
2011 FOXL2 upregulation promotes G1 cell-cycle arrest, protects granulosa cells from oxidative damage by promoting oxidized DNA repair and increasing glutathione, and modulates cell-cycle regulator expression; the SIRT1 deacetylase suppresses FOXL2 activity on cell-cycle and DNA repair targets in a dose-dependent manner Functional genomics, cell-cycle analysis (FACS), oxidative stress assays, deacetylase inhibitor experiments, comparison of BPES mutation classes Human molecular genetics High 21289058
2011 In Foxl2 mutant mouse pituitaries, gonadotrope specification is normal but FSHβ expression is severely impaired; activin-induced FSHβ expression and FSH secretion are abolished in primary pituitary cultures from Foxl2 mutant mice, demonstrating that FoxL2 is required for the activin-dependent activation of Fshb transcription Foxl2 mutant mouse analysis, primary pituitary cell cultures, hormone measurement, RT-PCR Molecular endocrinology High 21700720
2011 FOXL2 synergizes with SMAD2, SMAD3, and SMAD4 to stimulate murine Fshb promoter activity; SMAD3-induced Fshb expression depends on endogenous FOXL2; both FOXL2 and SMAD3/4 must bind DNA at adjacent cis-elements (proximal FKH element and SMAD-binding element) for full activin induction of Fshb transcription Reporter assays in heterologous and homologous cells, site-directed mutagenesis of promoter elements, FOXL2-SMAD interaction studies Molecular endocrinology High 21622537
2009 In Foxl2-null mice, early testis genes (Inhbb, Dhh, Sox9) are upregulated and several novel ovarian genes are dysregulated during embryonic development; gene-dosage sensitivity is demonstrated by heterozygous Foxl2 loss; a Foxl2 transgene disrupts embryonic testis differentiation and upregulates female markers, supporting dose-dependent anti-testis action throughout ovary differentiation Transcriptome profiling of Foxl2 knockout and double-mutant ovaries, transgenic rescue, principal component analysis BMC developmental biology High 19538736
2014 Conditional knockout of Foxl2 in gonadotrope cells causes FSH deficiency, subfertility, and impaired activin-stimulated Fshb expression in primary cultures, establishing FOXL2 as the first gonadotrope-restricted transcription factor required for selective FSH synthesis in vivo Cre/lox conditional knockout, hormone assays, reproductive phenotyping, primary pituitary cultures Molecular endocrinology High 23340250
2014 Combined conditional deletion of Foxl2 and Smad4 in gonadotropes essentially abolishes FSH synthesis and causes female sterility phenotype comparable to Fshb-knockout mice, establishing SMAD4 and FOXL2 as essential master regulators of Fshb transcription in vivo Double conditional knockout mouse (Cre/lox), FSH measurement, fertility phenotyping FASEB journal High 24739304
2014 FOXL2 is required for normal gene regulation by steroid receptors in murine primary follicular cells; FOXL2 directly modulates Esr2 (estrogen receptor beta) expression through a newly identified intronic element; FOXL2 represses Sox9 both independently and through activation of ESR2, establishing a coherent feed-forward loop for ovarian maintenance Primary follicular cell isolation, ChIP-seq, reporter assays, loss-of-function analysis eLife High 25369636
2014 FOXL2 directly transactivates AMH transcription (confirmed by luciferase assay, EMSA, and ChIP); BPES-associated FOXL2 mutants fail to activate AMH; in vivo, ectopic FOXL2 prevents AMH-knockdown-accelerated follicle growth, demonstrating positive cross-regulation between FOXL2 and AMH in ovarian follicle reserve maintenance Luciferase reporter assay, EMSA, ChIP, in vivo mouse gene delivery Fertility and sterility High 24973035
2014 FOXL2 transcriptionally represses Sf1 by antagonizing WT1-KTS activation of the Sf1 proximal promoter; a conserved FOXL2 binding site was identified by ChIP; mutations abolishing this site eliminate FOXL2-mediated repression; in Foxl2-null mice, Sf1 expression is increased 2-fold in XX fetal gonads Reporter assays, ChIP, site-directed mutagenesis, Foxl2-null mouse analysis FASEB journal High 24451388
2014 The C134W FOXL2 mutation undergoes differential post-translational modifications compared to wild-type: GSK3β hyperphosphorylates C134W at serine 33, inducing MDM2-mediated ubiquitination and proteasomal degradation; wild-type FOXL2 is underphosphorylated at S33, leading to SUMOylation and stabilization; S33 phosphorylation status correlates with GCT oncogenicity in xenograft mice, and GSK3β inhibition represses GCT growth In vitro kinase assays, mutagenesis, ubiquitination and SUMOylation assays, xenograft mouse model, patient tissue analysis Nature communications High 24390485
2005 FOXL2 interacts with DP103 (a DEAD-box RNA helicase) and induces apoptosis in CHO cells and rat granulosa cells; DP103 co-expression potentiates FOXL2-induced cell death Co-immunoprecipitation, overexpression in CHO and granulosa cells, cell viability assays Biochemical and biophysical research communications Medium 16153597
2009 Foxl2 suppresses ERα-mediated transcription through nonclassical (AP1-tethered) pathways but has no effect on classical ERE-dependent ERα transcription; Foxl2 physically interacts with ERα (co-IP); Foxl2 represses COX2 expression induced by ERα/tamoxifen signaling Reporter assays (AP1 and ERE), co-IP, expression profiling, western blotting Endocrinology Medium 19797124
2012 FOXL2 directly stimulates the clusterin (Clu) gene promoter in pituitary gonadotroph cells; FOXL2 also binds and suppresses the PTTG promoter; together, FOXL2 and Clu restrain pituitary gonadotroph tumor cell proliferation by inducing CDK inhibitors p16 and p27; in vivo, gonadotroph xenografts overexpressing Clu and FOXL2 grow slower Reporter assays, ChIP (implied by direct stimulation claim), xenograft mouse model, cell proliferation assays Molecular endocrinology Medium 23051594
2013 Wild-type FOXL2 (but not C134W mutant) induces follistatin production in KGN cells, and exogenous follistatin blocks activin A-stimulated cell proliferation; thus wild-type FOXL2 acts as a tumor suppressor by inducing follistatin that antagonizes activin-stimulated granulosa cell proliferation FOXL2 overexpression, follistatin ELISA/western blotting, exogenous follistatin rescue, KGN cell proliferation assays Biochemical and biophysical research communications Medium 24332943
2012 FOXL2 is involved in activin/progestin synergy on the Fshb promoter; FOXL2 physically interacts with progesterone receptor (PR) and SMAD3; multiple Fshb promoter elements binding FOXL2, SMADs, and PR are required for full synergistic response Reporter assays, co-IP, promoter mutagenesis Endocrinology Medium 22294749
2018 Genome-wide ChIP-seq of FOXL2 in fetal mouse ovaries shows extensive overlap with SOX9 occupancy in the fetal testis; ectopic FOXL2 expression in fetal testis somatic precursors represses Sertoli cell differentiation and causes partial testis-to-ovary sex reversal, demonstrating FOXL2 is sufficient to feminize the gonad ChIP-seq, gain-of-function transgenic mouse model, transcriptomic analysis Human molecular genetics High 30212841
2019 RUNX1 plays complementary/redundant roles with FOXL2 in maintaining fetal granulosa cell identity; combined loss of RUNX1 and FOXL2 results in masculinization of fetal ovaries; ChIP-seq shows RUNX1 occupancy partially overlaps with FOXL2 occupancy in fetal ovary, suggesting co-regulation of common gene targets Double conditional knockout mouse, ChIP-seq, single-cell transcriptomics Nature communications High 31712577
2020 The FOXL2 C134W mutant acquires the ability to bind SMAD4, forming a novel FOXL2C134W/SMAD4/SMAD2/3 complex that binds a hybrid DNA motif (AGHCAHAA) unique to the mutant; this binding induces an enhancer-like chromatin state activating nearby genes associated with EMT; ablation of SMAD4 or SMAD2/3 strongly reduces FOXL2C134W binding at hybrid sites ChIP-seq, co-IP, CRISPR ablation of SMAD4/SMAD2/3, chromatin state analysis, transcriptomics in primary AGCT Cancer research High 32641411
2020 The FOXL2 C134W mutation alters DNA-binding specificity genome-wide; FOXL2C134W associates with the majority of wild-type FOXL2 binding sites as well as a large set of unique sites; altered binding drives an oncogenic transcriptional program including SLC35F2 upregulation, which increases sensitivity to YM155 ChIP-seq and transcriptome profiling in V5-FOXL2WT vs. V5-FOXL2C134W isogenic inducible cell lines Cancer research High 32641414
2020 The FOXL2 C134W somatic mutation introduces a target site for miR-1236 in the coding sequence; miR-1236 selectively degrades variant FOXL2 mRNA via a non-canonical miRISC directed by AGO3 and DHX9, causing haploinsufficiency of tumor-suppressor FOXL2 in AGCTs miRNA target site mutagenesis, AGO3/DHX9 co-IP, miR-1236 gain/loss-of-function, patient sample correlation, mouse AGCT model EMBO journal High 33215742
2015 Conditional deletion of Foxl2 in the postnatal uterus using Pgr-cre results in infertility, reduced stromal thickness, hypertrophic/disorganized inner myometrial layer, failure of vascular smooth muscle organization, and deregulation of Wnt signaling genes, demonstrating a role for FOXL2 in uterine maturation Conditional knockout mouse (Pgr-cre; Foxl2flox/flox), histological analysis, gene expression profiling Human molecular genetics High 25687138
2018 Conditional deletion of both Foxl2 and Smad4 in gonadotrope cells of adult mice (using tamoxifen-inducible Cre) causes profound FSH reduction, arrested ovarian follicle development, and sterility, demonstrating that FOXL2 and SMAD4 are continuously required for FSH synthesis in adult gonadotropes Tamoxifen-inducible conditional double KO, FSH ELISA, histological analysis of ovaries Endocrinology High 29800110
2015 Foxl2-null mice show defects in postnatal growth, embryonic bone and cartilage formation, and down-regulation of the GH/IGF1 axis; FOXL2 is expressed in neural tube epithelium, head mesenchyme, cartilaginous tissue, and hypothalamus during development; FOXL2 and SOX9 act jointly in cartilage development despite being antagonistic in gonadal sex determination Foxl2 knockout mouse, skeletal staining, immunofluorescence, microarray, RT-qPCR for GH/IGF1 pathway BMC developmental biology Medium 26134413
2022 Lineage tracing of Foxl2-expressing cells in fetal mouse ovaries reveals that they are multipotent, giving rise not only to granulosa cells but also to theca-interstitial cells (Theca-G) and stromal cells; single-cell RNA-seq shows two FOXL2-positive clusters at P0, one differentiating into granulosa/Theca-G and another into stromal/Theca-S lineages Genetic lineage tracing (Cre/Rosa reporter), single-cell RNA-seq across developmental time points Cell discovery High 36575161

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 603 19516027
2004 The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development (Cambridge, England) 579 14736745
2007 Loss of Wnt4 and Foxl2 leads to female-to-male sex reversal extending to germ cells. Human molecular genetics 249 17728319
2001 Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation. Human molecular genetics 213 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 187 20693978
2011 FOXL2 is a sensitive and specific marker for sex cord-stromal tumors of the ovary. The American journal of surgical pathology 148 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 132 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 130 28119367
2006 Molecular cloning and analysis of gonadal expression of Foxl2 in the medaka, Oryzias latipes. Biochemical and biophysical research communications 126 16630569
2010 Mutational analysis of FOXL2 codon 134 in granulosa cell tumour of ovary and other human cancers. The Journal of pathology 119 20198651
2006 FOXL2 in the pituitary: molecular, genetic, and developmental analysis. Molecular endocrinology (Baltimore, Md.) 111 16840539
2009 Foxl2 functions in sex determination and histogenesis throughout mouse ovary development. BMC developmental biology 108 19538736
2003 Structure, evolution and expression of the FOXL2 transcription unit. Cytogenetic and genome research 107 14684984
2010 FOXL2 interacts with steroidogenic factor-1 (SF-1) and represses SF-1-induced CYP17 transcription in granulosa cells. Molecular endocrinology (Baltimore, Md.) 102 20207836
2005 Aromatase inhibition reduces expression of FOXL2 in the embryonic chicken ovary. Developmental dynamics : an official publication of the American Association of Anatomists 99 15830351
2009 FOXL2 mutations and genomic rearrangements in BPES. Human mutation 97 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 97 18348162
2008 FoxL2 and Smad3 coordinately regulate follistatin gene transcription. The Journal of biological chemistry 94 19106105
2015 DICER1 and FOXL2 mutations in ovarian sex cord-stromal tumours: a GINECO Group study. Histopathology 86 26033501
2014 The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells. eLife 86 25369636
2011 Minireview: roles of the forkhead transcription factor FOXL2 in granulosa cell biology and pathology. Endocrinology 85 21248146
2009 The specificity of the FOXL2 c.402C>G somatic mutation: a survey of solid tumors. PloS one 83 19956657
2004 A recurrent polyalanine expansion in the transcription factor FOXL2 induces extensive nuclear and cytoplasmic protein aggregation. Journal of medical genetics 82 15591279
2017 Sex determination and maintenance: the role of DMRT1 and FOXL2. Asian journal of andrology 75 28091399
2011 Transcription factor FOXL2 protects granulosa cells from stress and delays cell cycle: role of its regulation by the SIRT1 deacetylase. Human molecular genetics 74 21289058
2019 RUNX1 maintains the identity of the fetal ovary through an interplay with FOXL2. Nature communications 73 31712577
2013 Microhomology-mediated mechanisms underlie non-recurrent disease-causing microdeletions of the FOXL2 gene or its regulatory domain. PLoS genetics 72 23516377
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 68 24739304
2011 The transcription factor FOXL2: at the crossroads of ovarian physiology and pathology. Molecular and cellular endocrinology 67 21763750
2010 Functional exploration of the adult ovarian granulosa cell tumor-associated somatic FOXL2 mutation p.Cys134Trp (c.402C>G). PloS one 66 20098707
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
2013 Impaired fertility and FSH synthesis in gonadotrope-specific Foxl2 knockout mice. Molecular endocrinology (Baltimore, Md.) 61 23340250
2007 Extinction of FOXL2 expression in aggressive ovarian granulosa cell tumors in children. Fertility and sterility 60 17430735
2006 A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction. Human genetics 58 17089161
2005 Transcriptional factor FOXL2 interacts with DP103 and induces apoptosis. Biochemical and biophysical research communications 58 16153597
2011 SMADs and FOXL2 synergistically regulate murine FSHbeta transcription via a conserved proximal promoter element. Molecular endocrinology (Baltimore, Md.) 56 21622537
2008 R-spondin1 and FOXL2 act into two distinct cellular types during goat ovarian differentiation. BMC developmental biology 55 18384673
2007 The mutations and potential targets of the forkhead transcription factor FOXL2. Molecular and cellular endocrinology 55 18155828
2012 WNT4, RSPO1, and FOXL2 in sex development. Seminars in reproductive medicine 54 23044875
2021 Germline sexual fate is determined by the antagonistic action of dmrt1 and foxl3/foxl2 in tilapia. Development (Cambridge, England) 52 33741713
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
2011 Loss of R-spondin1 and Foxl2 amplifies female-to-male sex reversal in XX mice. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 49 22116255
2016 WNT/β-catenin and p27/FOXL2 differentially regulate supporting cell proliferation in the developing ovary. Developmental biology 48 26939755
2018 Genome-wide identification of FOXL2 binding and characterization of FOXL2 feminizing action in the fetal gonads. Human molecular genetics 47 30212841
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 44 32641411
2012 FOXL2 mutations in granulosa cell tumors occurring in males. Archives of pathology & laboratory medicine 44 22742556
2009 FOXL2 mutations lead to different ovarian phenotypes in BPES patients: Case Report. Human reproduction (Oxford, England) 44 19819892
2021 Functional Divergence of Multiple Duplicated Foxl2 Homeologs and Alleles in a Recurrent Polyploid Fish. Molecular biology and evolution 43 33432361
2018 FOXL2 and DMRT1L Are Yin and Yang Genes for Determining Timing of Sex Differentiation in the Bivalve Mollusk Patinopecten yessoensis. Frontiers in physiology 42 30246781
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 41 24451388
2020 Phytoestrogen genistein hinders ovarian oxidative damage and apoptotic cell death-induced by ionizing radiation: co-operative role of ER-β, TGF-β, and FOXL-2. Scientific reports 38 32782329
2019 Adult Granulosa Cell Tumor With High-grade Transformation: Report of a Series With FOXL2 Mutation Analysis. The American journal of surgical pathology 38 31162286
2014 FOXL2 posttranslational modifications mediated by GSK3β determine the growth of granulosa cell tumours. Nature communications 37 24390485
2011 FTZ-F1 and FOXL2 up-regulate catfish brain aromatase gene transcription by specific binding to the promoter motifs. Biochimica et biophysica acta 37 22019437
2017 Testis Determination Requires a Specific FGFR2 Isoform to Repress FOXL2. Endocrinology 36 28938467
2014 Molecular cloning and analysis of gonadal expression of Foxl2 in the rice-field eel Monopterus albus. Scientific reports 36 25363394
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 34 24973035
2019 FOXL2 antagonises the male developmental pathway in embryonic chicken gonads. The Journal of endocrinology 33 31505465
2011 Impaired FSHbeta expression in the pituitaries of Foxl2 mutant animals. Molecular endocrinology (Baltimore, Md.) 33 21700720
2009 Xenopus W-linked DM-W induces Foxl2 and Cyp19 expression during ovary formation. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 33 19339816
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
2005 Sense and antisense Foxl2 transcripts in mouse. Genomics 30 15820304
2021 The Genetics and Biology of FOXL2. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 29 34727551
2013 The role of FOXL2 in the pathogenesis of adult ovarian granulosa cell tumours. Gynecologic oncology 29 24342437
2010 Expression and localization of forkhead transcriptional factor 2 (Foxl2) in the gonads of protogynous wrasse, Halichoeres trimaculatus. Biology of sex differences 29 21208465
2019 Roles of forkhead box protein L2 (foxl2) during gonad differentiation and maintenance in a fish, the olive flounder (Paralichthys olivaceus). Reproduction, fertility, and development 28 31537253
2009 Foxl2, a forkhead transcription factor, modulates nonclassical activity of the estrogen receptor-alpha. Endocrinology 28 19797124
2003 FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients. American journal of medical genetics. Part A 28 12567411
1996 Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). Acta ophthalmologica Scandinavica 28 8689480
2002 Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families. American journal of medical genetics 27 12400065
2015 microRNA133a targets Foxl2 and promotes differentiation of C2C12 into myogenic progenitor cells. DNA and cell biology 26 25317675
2012 Clusterin and FOXL2 act concordantly to regulate pituitary gonadotroph adenoma growth. Molecular endocrinology (Baltimore, Md.) 26 23051594
2018 Conditional Deletion of FOXL2 and SMAD4 in Gonadotropes of Adult Mice Causes Isolated FSH Deficiency. Endocrinology 25 29800110
2015 FOXL2 down-regulates vitellogenin expression at mature stage in Eriocheir sinensis. Bioscience reports 25 26430246
2022 Dissecting the fate of Foxl2-expressing cells in fetal ovary using lineage tracing and single-cell transcriptomics. Cell discovery 24 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 24 28319575
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
2012 FOXL2 is involved in the synergy between activin and progestins on the follicle-stimulating hormone β-subunit promoter. Endocrinology 23 22294749
2021 Rare DICER1 and Absent FOXL2 Mutations Characterize Ovarian Juvenile Granulosa Cell Tumors. The American journal of surgical pathology 22 32910017
2015 FOXL2 modulates cartilage, skeletal development and IGF1-dependent growth in mice. BMC developmental biology 22 26134413
2013 FOXL2-induced follistatin attenuates activin A-stimulated cell proliferation in human granulosa cell tumors. Biochemical and biophysical research communications 22 24332943
2012 FOXL2 is regulated during the bovine estrous cycle and its expression in the endometrium is independent of conceptus-derived interferon tau. Biology of reproduction 22 22623620
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
2008 Differential functional effects of novel mutations of the transcription factor FOXL2 in BPES patients. Human mutation 22 18484667
2021 Characterization of the foxl2 gene involved in the vtg expression in mud crab (Scylla paramamosain). Gene 21 34224832
2014 FOXL2 suppresses proliferation, invasion and promotes apoptosis of cervical cancer cells. International journal of clinical and experimental pathology 21 24817949
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
1996 Refined genetic and physical mapping of BPES type II. European journal of human genetics : EJHG 21 8800926
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