FOXL2


Forkhead box protein L2 is a protein that in humans is encoded by the FOXL2 gene.

Function

FOXL2 is a forkhead transcription factor. The protein contains a fork-head DNA-binding domain and plays a role in ovarian development and function. FoxL2 is a marker for ovarian differentiation and is required for granulosa cell differentiation. In addition, the foxl2 protein will prevent the formation of testes by suppressing expression of SOX9.
In postnatal ovaries, FOXL2 regulates granulosa cell differentiation and also supports the growth of the pre-ovulatory follicles during adult life.

Regulation

FOXL2 has several post-translational modifications that modulate its stability, subcellular localization and pro-apoptotic activity. By a yeast-two-hybrid screening, 10 novel protein partners of FOXL2 were discovered. The interactions were confirmed by co-immunoprecipitation experiments between FOXL2 and CXXC4, CXXC5, CREM, GMEB1, NR2C1, SP100, RPLP1, BAF, XRCC6 and SIRT1.

Clinical significance

Sex determination

FOXL2 is involved in sex determination. Females missing the FOXL2 gene appear male. FOXL2 knockout in mature mouse ovaries appears to cause the ovary's somatic cells to transdifferentiate to the equivalent cell types ordinarily found in the testes.

Eyebrow thickness

A variant on FOXL2 is the single most significant in producing thicker than average eyebrows. In Europeans, East Asians, and South Asians, the derived allele is above ~90% frequency, and in Africans, it is above ~75%. Native Americans, particularity Peruvians, have a relatively high frequency of the homozygous ancestral allele, which significantly decreases eyebrow thickness. All primates and archaic humans share the ancestral allele.

Blepharophimosis–ptosis–epicanthus inversus syndrome

Mutations in this gene are a cause of blepharophimosis, ptosis, epicanthus inversus syndrome and/or premature ovarian failure 3. Predicting the occurrence of POF based on the nature of the missense mutations in FOXL2 was a medical challenge. However, a correlation between the transcriptional activity of FOXL2 variants and the type of BPES was found. Moreover, by studying the effects of natural and artificial mutations in the forkhead domain of FOXL2, a clear correlation between the orientation of amino-acid side chains in the DNA-binding domain and transcriptional activity is founded, providing the first predictive tool of the effects of FOXL2 missense mutations.

Granulosa Cell Tumors AGCT">Adult granulosa cell tumors

A missense mutation in the FOXL2 gene, C134W, is found in adult granulosa cell tumors but not in other ovarian cancers nor in juvenile granulosa cell tumors.

Endometriosis

In addition to ovarian expression of FOXL2, there has been recent studies to suggest that overexpression of FOXL2 has been implicated in endometriosis in addition to activin A.

Other deregulations

One study has found that FOXL2 is required for SF-1-induced ovarian AMH regulation by interactions between FOXL2 protein and SF-1; a mutated FOXL2 could not interact with SF-1 normally and thus could not regulate ovarian AMH as normal.
In a knockout study in mice, the granulosa cells of the ovaries failed to undergo the squamous-to-cuboidal transition, which led to the arrest of folliculogenesis.