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FLASH GENE
Symbol FOXL2 contributors: mct/shn - updated : 12-10-2022
HGNC name forkhead box L2
HGNC id 1092
DNA
TYPE functioning gene
SPECIAL FEATURE
text opposite orientation with PFOXIC
STRUCTURE 2.91 kb     1 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Binding site
text structure
  • bidirectional promoter activity (also for PFOXIC)
  • a FoxL2 response element (FLRE)
    • MAPPING cloned Y linked Y status provisional
    Map cen - D3S4544 - D3S1576 - FOXL2 - D3S3586 - D3S2435 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    1 - 2917 - 376 - 2022 35920317
    EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Reproductivefemale systemovary    Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialsecretoryglandularendocrine 
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Reproductiveepithelial cell Homo sapiens
    Reproductivegranulosa cell Homo sapiens
    Reproductiveoocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, fetal
    Text mesenchyme of developing eyelids, fetal ovarian follicular and stromal cells
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a characteristic DNA-binding domain called forkhead (FHD)
  • a polyAlanine domain of 14 AAs
  • two loops-wings on the C terminal side of helix-turn-helix homeo domain
    • HOMOLOGY
    interspecies homolog to Pfrk
    ortholog to Foxl2, Mus musculus
    ortholog to Foxl2, Rattus norvegicus
    ortholog to FOX2, Pan troglodytes
    ortholog to foxl2, Danio rerio
    Homologene
    FAMILY
  • HNF-3 forkhead family of transcriptional activators
    • CATEGORY regulatory , DNA associated , transcription factor , protooncogene
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    text polyalanine expansion inducing extensive nuclear and cytoplasmic protein aggregation, and retaining normal protein in the cytoplasm
    basic FUNCTION
  • transcriptional regulator of ovarian function and eyelid development via the inhibin/activin signaling pathway
  • playing a multiple role during fetal development and also latter during adult female fertility life
  • crucial actor in the ovarian differentiation process in different vertebrate species
  • playing a role in regulation of glycoprotein hormone alpha-subunit gene expression
  • playing a crucial role in ovarian development and maintenance
  • actor of the stress response
  • may play a role throughout female fertile life in follicular maturation and/or maintenance
  • able to directly activate SIRT1 transcription
  • induces significant granulosa cell death while the mutant version exhibited a minimal activity
  • essential for ovarian function and maintenance
  • may play a key role in granulosa cell homeostasis, the failure of which is central to ovarian ageing and tumorigenesis
  • key role for FOXL2 in the control of granulosa cell proliferation and stress response
  • central role of FOXL2 is the lifetime maintenance of granulosa cell (GC) identity through the repression of testis-specific genes
  • is a transcription factor that plays a critical role in ovarian function, in particular, proliferation and differentiation of granulosa cells
  • FOXL2 is an essential activator of NR5A1-induced transcriptional regulation of anti-müllerian hormone in granulosa cells
  • transcription factor that also plays a crucial role in folliculogenesis and ovarian fate maintenance in adults
  • RUNX1 plays complementary/redundant roles with FOXL2 to maintain fetal granulosa cell identity and combined loss of RUNX1 and FOXL2 results in masculinization of fetal ovaries
  • regulates sex differentiation and reproductive function
    • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS development
    text eyelids, maintenance of ovarian follicles
    PATHWAY
    metabolism
    signaling sensory transduction/vision
    a component
    INTERACTION
    DNA
  • direct transcriptional activator of the CYP19A1 gene through its ovarian-specific promoter 2
  • forkhead-binding element located just downstream of the SBE1 site of the follistatin gene (
    • RNA
    small molecule
    protein
  • DEAD box protein DP 103, DP103 (
  • FSHB interacting with FOXL2 (novel role for FOXL2 in activin A-regulated FSHB transcription)
  • Smad3
  • ubiquitin-conjugating enzyme E2I, UBE2I
  • antagonism between DMRT1 and FOXL2 for control of gonadal sex may therefore extend beyond mammals
  • DMRT1 maintains SOX9 and suppresses FOXL2 expression in postnatal Sertoli cells
  • SMAD4 and FOXL2 are essential master regulators of FSHB transcription
  • SMAD4 and FOXL2 are master transcriptional mediators of activin signaling that act together and independently of GNRH to regulate FSHB gene expression and female fertility
  • FOXL2 may be regulated by STAT3
  • FOXL2 and SMAD4 play essential roles in human FSHB expression
  • many of the FOXL2/ESR2 targets are involved in cell motility and, consistently, granulosa cells depleted for either FOXL2 or ESR2 exhibit decreased migration, invasion and adhesion
    • cell & other
    REGULATION
    inhibited by SIRT1 (SIRT1 was able to inhibit FOXL2 transactivation and, eventually, its expression, we assessed the effect of nicotinamide on FOXL2 activity and expression)
    SIRT1 (its activity can be inhibited by SIRT1, which modulates its ability to regulate stress-related genes)
    ASSOCIATED DISORDERS
    corresponding disease(s) BPES , POF3
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    mutation in premature ovarian failure
    tumoral somatic mutation      
    leading to a p.C134W change, was found in the majority of adult-type ovarian granulosa cell tumors (GCTs)
    constitutional       gain of function
    promotes cell accumulation in G1 phase and protects cells from oxidative damage
    constitutional     --other  
    aberrantly increased FOXL2 expressions in the female reproductive tract can disrupt ovarian and uterine functions
    constitutional       loss of function
    dysregulated FOXL2 function may alter cell cycle progression and apoptosis
    constitutional     --over  
    in endometriosis, suggesting an involvement of this transcriptional regulator, probably associated with activin A expression and related to the pathogenesis of endometriosis
    Susceptibility to isolated premature ovarian failure (POF)
    Variant & Polymorphism other variant detected in a POF case without BPES
    Candidate gene female sex determining
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • mice lacking Foxl2 display gonadal dysgenesis, are small and show distinctive craniofacial morphology with upper eyelids absent (
  • Inducible deletion of Foxl2 in adult ovarian mouse follicles leads to immediate upregulation of testis-specific genes including the critical SRY target gene Sox9 (
  • Foxl2-null mice exhibit developmental defects in granulosa cells