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FLASH GENE

Symbol

FOXL2

contributors: mct/shn - updated : 12-10-2022

HGNC name	forkhead box L2
HGNC id	1092

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Reproductive female system ovary       Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine

cells

System Cell Pubmed Species Stage Rna symbol Reproductive epithelial cell Homo sapiens Reproductive granulosa cell Homo sapiens Reproductive oocyte

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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