Biology:FOXL2

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Short description: Transcription factor gene of the FOX family


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Forkhead box protein L2 is a protein that in humans is encoded by the FOXL2 gene.[1][2]

Function

FOXL2 (OMIM 605597) is a transcription factor belonging to the forkhead box (FOX) superfamily, characterized by the forkhead box/winged-helix DNA-binding domain. FOXL2 plays an important role in ovarian development and function.[2] In postnatal ovaries FOXL2 regulates granulosa cell differentiation and supports the growth of the pre-ovulatory follicles during adult life.[3] In addition, the FOXL2 protein will prevent the formation of testes by suppressing expression of SOX9.[4] In mice, FOXL2 is also expressed in pituitary cells[5] where it is required for FSH expression.[6]

Regulation

FOXL2 has several post-translational modifications that modulate its stability, subcellular localization and pro-apoptotic activity.[7] 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 (IDAX), CXXC5 (RINF/WID), CREM, GMEB1 (P96PIF), NR2C1 (TR2), SP100, RPLP1, BAF (BANF1), XRCC6 (KU70) and SIRT1.[8]

Clinical significance

Sex determination

FOXL2 is involved in sex determination. 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.[9] Polled Intersex Syndrome in goats is caused by a biallelic loss-of-function in FOXL2 transcription and leads to in utero female-to-male sex-reversal.[10]

Eyebrow thickness

Several SNPs (Single Variant Polymorphisms) in the genomic region 3q23 overlapping the forkhead box L2 (FOXL2) were found associated with eyebrow thickness. In Europeans, East Asians, and South Asians, the derived allele is above ~90% frequency, and in Africans, it is above ~75%. Native Americans, particularly 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.[11]

Blepharophimosis–ptosis–epicanthus inversus syndrome

Mutations in this gene are a cause of blepharophimosis, ptosis, epicanthus inversus syndrome and/or premature ovarian failure (POF) 3.[2] 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.[12] 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 (in silico) predictive tool of the effects of FOXL2 missense mutations.[13]

Adult granulosa cell tumors

A missense mutation in the FOXL2 gene, C134W, is typically found in adult granulosa cell tumors but not in other ovarian cancers nor in juvenile granulosa cell tumors.[3]

Endometriosis

In addition to ovarian expression of FOXL2, there have been recent studies to suggest that overexpression of FOXL2 has been implicated in endometriosis in addition to activin A.[14]

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.[15]

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.[16]

See also

References

  1. ↑ "Further evidence for the location of the BPES gene at 3q2". Journal of Medical Genetics 28 (10): 725. October 1991. doi:10.1136/jmg.28.10.725. PMID 1941972. 
  2. ↑ 2.0 2.1 2.2 "Entrez Gene: FOXL2 forkhead box L2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=668. 
  3. ↑ 3.0 3.1 "Impact of FOXL2 mutations on signaling in ovarian granulosa cell tumors". The International Journal of Biochemistry & Cell Biology 72: 51–4. March 2016. doi:10.1016/j.biocel.2016.01.003. PMID 26791928. 
  4. ↑ "Sequential, Divergent, and Cooperative Requirements of Foxl2a and Foxl2b in Ovary Development and Maintenance of Zebrafish". Genetics 205 (4): 1551–1572. April 2017. doi:10.1534/genetics.116.199133. PMID 28193729. 
  5. ↑ "FOXL2 in the pituitary: molecular, genetic, and developmental analysis". Mol Endocrinol 20 (11): 2796–805. November 2006. doi:10.1210/me.2005-0303. PMID 16840539. 
  6. ↑ "Impaired FSHbeta expression in the pituitaries of Foxl2 mutant animals". Mol Endocrinol 25 (8): 1404–15. August 2011. doi:10.1210/me.2011-0093. PMID 21700720. 
  7. ↑ "SUMOylation of the Forkhead transcription factor FOXL2 promotes its stabilization/activation through transient recruitment to PML bodies". PLOS ONE 6 (10): e25463. Oct 2011. doi:10.1371/journal.pone.0025463. PMID 22022399. Bibcode: 2011PLoSO...625463G. 
  8. ↑ "Discovery of novel protein partners of the transcription factor FOXL2 provides insights into its physiopathological roles". Human Molecular Genetics 21 (14): 3264–74. July 2012. doi:10.1093/hmg/dds170. PMID 22544055. 
  9. ↑ "Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation". Cell 139 (6): 1130–42. December 2009. doi:10.1016/j.cell.2009.11.021. PMID 20005806. *Lay summary in: "Ovaries reveal their inner testes". December 10, 2009. http://www.nature.com/news/2009/091210/full/news.2009.1135.html. 
  10. ↑ "FOXL2 is a female sex-determining gene in the goat". Curr Biol 24 (4): 404–8. February 2014. doi:10.1016/j.cub.2013.12.039. PMID 24485832. 
  11. ↑ "A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features". Nature Communications 7: 10815. March 2016. doi:10.1038/ncomms10815. PMID 26926045. Bibcode: 2016NatCo...710815A. 
  12. ↑ "Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems". Human Molecular Genetics 18 (17): 3324–33. September 2009. doi:10.1093/hmg/ddp273. PMID 19515849. 
  13. ↑ "Mutational probing of the forkhead domain of the transcription factor FOXL2 provides insights into the pathogenicity of naturally occurring mutations". Human Molecular Genetics 20 (17): 3376–85. September 2011. doi:10.1093/hmg/ddr244. PMID 21632871. 
  14. ↑ "FOXL2 in human endometrium: hyperexpressed in endometriosis" (in en). Reproductive Sciences 21 (10): 1249–55. October 2014. doi:10.1177/1933719114522549. PMID 24520083. 
  15. ↑ "FOXL2 Is an Essential Activator of SF-1-Induced Transcriptional Regulation of Anti-Müllerian Hormone in Human Granulosa Cells". PLOS ONE 11 (7): e0159112. 2016-07-14. doi:10.1371/journal.pone.0159112. PMID 27414805. Bibcode: 2016PLoSO..1159112J. 
  16. ↑ "The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance" (in en). Development 131 (4): 933–42. February 2004. doi:10.1242/dev.00969. PMID 14736745. 

Further reading

External links



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