FOXL2 explained

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. 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

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

• FOX proteins

Further reading

• Vaiman D, Schibler L, Oustry-Vaiman A, Pailhoux E, Goldammer T, Stevanovic M, Furet JP, Schwerin M, Cotinot C, Fellous M, Cribiu EP . High-resolution human/goat comparative map of the goat polled/intersex syndrome (PIS): the human homologue is contained in a human YAC from HSA3q23 . Genomics . 56 . 1 . 31–9 . February 1999 . 10036183 . 10.1006/geno.1998.5691 . 1446666 .
• Kaestner KH, Knochel W, Martinez DE . Unified nomenclature for the winged helix/forkhead transcription factors . Genes & Development . 14 . 2 . 142–6 . January 2000 . 10702024 . 10.1101/gad.14.2.142 . 26488600 . free .
• Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, Bisceglia L, Zelante L, Nagaraja R, Porcu S, Ristaldi MS, Marzella R, Rocchi M, Nicolino M, Lienhardt-Roussie A, Nivelon A, Verloes A, Schlessinger D, Gasparini P, Bonneau D, Cao A, Pilia G . The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome . Nature Genetics . 27 . 2 . 159–66 . February 2001 . 11175783 . 10.1038/84781 . 26750194 .
• De Baere E, Dixon MJ, Small KW, Jabs EW, Leroy BP, Devriendt K, Gillerot Y, Mortier G, Meire F, Van Maldergem L, Courtens W, Hjalgrim H, Huang S, Liebaers I, Van Regemorter N, Touraine P, Praphanphoj V, Verloes A, Udar N, Yellore V, Chalukya M, Yelchits S, De Paepe A, Kuttenn F, Fellous M, Veitia R, Messiaen L . Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation . Human Molecular Genetics . 10 . 15 . 1591–600 . July 2001 . 11468277 . 10.1093/hmg/10.15.1591 . free .
• Dollfus H, Kumaramanickavel G, Biswas P, Stoetzel C, Quillet R, Denton M, Maw M, Perrin-Schmitt F . Identification of a new TWIST mutation (7p21) with variable eyelid manifestations supports locus homogeneity of BPES at 3q22 . Journal of Medical Genetics . 38 . 7 . 470–2 . July 2001 . 11474656 . 1757180 . 10.1136/jmg.38.7.470 .
• Yamada T, Hayasaka S, Matsumoto M, Esa T, Hayasaka Y, Endo M . Heterozygous 17-bp deletion in the forkhead transcription factor gene, FOXL2, in a Japanese family with blepharophimosis-ptosis-epicanthus inversus syndrome . Journal of Human Genetics . 46 . 12 . 733–6 . 2002 . 11776388 . 10.1007/s100380170009 . 39171567 . free .
• Kosaki K, Ogata T, Kosaki R, Sato S, Matsuo N . A novel mutation in the FOXL2 gene in a patient with blepharophimosis syndrome: differential role of the polyalanine tract in the development of the ovary and the eyelid . Ophthalmic Genetics . 23 . 1 . 43–7 . March 2002 . 11910558 . 10.1076/opge.23.1.43.2202 . 2502871 .
• Bell R, Murday VA, Patton MA, Jeffery S . Two families with blepharophimosis/ptosis/epicanthus inversus syndrome have mutations in the putative forkhead transcription factor FOXL2 . Genetic Testing . 5 . 4 . 335–8 . 2002 . 11960581 . 10.1089/109065701753617499 .
• Harris SE, Chand AL, Winship IM, Gersak K, Aittomäki K, Shelling AN . Identification of novel mutations in FOXL2 associated with premature ovarian failure . Molecular Human Reproduction . 8 . 8 . 729–33 . August 2002 . 12149404 . 10.1093/molehr/8.8.729 . free .
• De Baere E, Lemercier B, Christin-Maitre S, Durval D, Messiaen L, Fellous M, Veitia R . FOXL2 mutation screening in a large panel of POF patients and XX males . Journal of Medical Genetics . 39 . 8 . 43e–43 . August 2002 . 12161610 . 1735205 . 10.1136/jmg.39.8.e43 .
• Ramírez-Castro JL, Pineda-Trujillo N, Valencia AV, Muñetón CM, Botero O, Trujillo O, Vásquez G, Mora BE, Durango N, Bedoya G, Ruiz-Linares A . Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families . American Journal of Medical Genetics . 113 . 1 . 47–51 . November 2002 . 12400065 . 10.1002/ajmg.10741 .
• Cocquet J, Pailhoux E, Jaubert F, Servel N, Xia X, Pannetier M, De Baere E, Messiaen L, Cotinot C, Fellous M, Veitia RA . Evolution and expression of FOXL2 . Journal of Medical Genetics . 39 . 12 . 916–21 . December 2002 . 12471206 . 1757225 . 10.1136/jmg.39.12.916 .
• De Baere E, Beysen D, Oley C, Lorenz B, Cocquet J, De Sutter P, Devriendt K, Dixon M, Fellous M, Fryns JP, Garza A, Jonsrud C, Koivisto PA, Krause A, Leroy BP, Meire F, Plomp A, Van Maldergem L, De Paepe A, Veitia R, Messiaen L . FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation . American Journal of Human Genetics . 72 . 2 . 478–87 . February 2003 . 12529855 . 379240 . 10.1086/346118 .
• Mazumdar A, Kumar R . Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells . FEBS Letters . 535 . 1–3 . 6–10 . January 2003 . 12560069 . 10.1016/S0014-5793(02)03846-2 . 28855687 . 2003FEBSL.535....6M .
• Fokstuen S, Antonarakis SE, Blouin JL . FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients . American Journal of Medical Genetics. Part A . 117A . 2 . 143–6 . March 2003 . 12567411 . 10.1002/ajmg.a.10024 . 41583322 .
• Dollfus H, Stoetzel C, Riehm S, Lahlou Boukoffa W, Bediard Boulaneb F, Quillet R, Abu-Eid M, Speeg-Schatz C, Francfort JJ, Flament J, Veillon F, Perrin-Schmitt F . Sporadic and familial blepharophimosis -ptosis-epicanthus inversus syndrome: FOXL2 mutation screen and MRI study of the superior levator eyelid muscle . Clinical Genetics . 63 . 2 . 117–20 . February 2003 . 12630957 . 10.1034/j.1399-0004.2003.00011.x . 19151109 .
• Udar N, Yellore V, Chalukya M, Yelchits S, Silva-Garcia R, Small K . Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients . Human Mutation . 22 . 3 . 222–8 . September 2003 . 12938087 . 10.1002/humu.10251 . 24771690 . free .
• Crisponi L, Uda M, Deiana M, Loi A, Nagaraja R, Chiappe F, Schlessinger D, Cao A, Pilia G . FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences . Genomics . 83 . 5 . 757–64 . May 2004 . 15081106 . 10.1016/j.ygeno.2003.11.010 .
• L'Hôte D, Georges A, Todeschini AL, Kim JH, Benayoun BA, Bae J, Veitia RA . 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 . 22544055 . 10.1093/hmg/dds170 . free .
• Georges A, L'Hôte D, Todeschini AL, Auguste A, Legois B, Zider A, Veitia RA . The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells . eLife . 3 . November 2014 . 25369636 . 10.7554/eLife.04207 . 4356143 . free .
• Elzaiat M, Todeschini AL, Caburet S, Veitia RA . The genetic make-up of ovarian development and function: the focus on the transcription factor FOXL2 . Clinical Genetics . 91 . 2 . 173–182 . February 2017 . 27604691 . 10.1111/cge.12862 . 30962804 . free .

External links

• • GeneReviews/NCBI/NIH/UW entry on Blepharophimosis, Ptosis, and Epicanthus Inversus

Notes and References

1. de Die-Smulders CE, Engelen JJ, Donk JM, Fryns JP . Further evidence for the location of the BPES gene at 3q2 . Journal of Medical Genetics . 28 . 10 . 725 . October 1991 . 1941972 . 1017067 . 10.1136/jmg.28.10.725 .
2. Web site: Entrez Gene: FOXL2 forkhead box L2.
3. Leung DT, Fuller PJ, Chu S . Impact of FOXL2 mutations on signaling in ovarian granulosa cell tumors . The International Journal of Biochemistry & Cell Biology . 72 . 51–4 . March 2016 . 26791928 . 10.1016/j.biocel.2016.01.003 .
4. Yang YJ, Wang Y, Li Z, Zhou L, Gui JF . Sequential, Divergent, and Cooperative Requirements of Foxl2a and Foxl2b in Ovary Development and Maintenance of Zebrafish . Genetics . 205 . 4 . 1551–1572 . April 2017 . 28193729 . 5378113 . 10.1534/genetics.116.199133 .
5. Ellsworth BS, Egashira N, Haller JL, Butts DL, Cocquet J, Clay CM, Osamura RY, Camper SA . FOXL2 in the pituitary: molecular, genetic, and developmental analysis . Mol Endocrinol . 20 . 11 . 2796–805 . November 2006 . 16840539 . 10.1210/me.2005-0303 . free .
6. Justice NJ, Blount AL, Pelosi E, Schlessinger D, Vale W, Bilezikjian LM . Impaired FSHbeta expression in the pituitaries of Foxl2 mutant animals . Mol Endocrinol . 25 . 8 . 1404–15 . August 2011 . 21700720 . 3146251 . 10.1210/me.2011-0093 .
7. Georges A, Benayoun BA, Marongiu M, Dipietromaria A, L'Hôte D, Todeschini AL, Auer J, Crisponi L, Veitia RA . SUMOylation of the Forkhead transcription factor FOXL2 promotes its stabilization/activation through transient recruitment to PML bodies . PLOS ONE . 6 . 10 . e25463 . Oct 2011 . 22022399 . 10.1371/journal.pone.0025463 . 3192040. 2011PLoSO...625463G . free .
8. L'Hôte D, Georges A, Todeschini AL, Kim JH, Benayoun BA, Bae J, Veitia RA . 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 . 22544055 . 10.1093/hmg/dds170 . free .
9. Uhlenhaut NH, Jakob S, Anlag K, Eisenberger T, Sekido R, Kress J, Treier AC, Klugmann C, Klasen C, Holter NI, Riethmacher D, Schütz G, Cooney AJ, Lovell-Badge R, Treier M . Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation . Cell . 139 . 6 . 1130–42 . December 2009 . 20005806 . 10.1016/j.cell.2009.11.021 . 14305820 . free .
10. Boulanger L, Pannetier M, Gall L, Allais-Bonnet A, Elzaiat M, Le Bourhis D, Daniel N, Richard C, Cotinot C, Ghyselinck NB, Pailhoux E. FOXL2 is a female sex-determining gene in the goat . Curr Biol . 24 . 4 . 404–8 . February 2014 . 24485832 . 10.1016/j.cub.2013.12.039 . 12076748. free . 2014CBio...24..404B .
11. Adhikari K, Fontanil T, Cal S, Mendoza-Revilla J, Fuentes-Guajardo M, Chacón-Duque JC, Al-Saadi F, Johansson JA, Quinto-Sanchez M, Acuña-Alonzo V, Jaramillo C, Arias W, Barquera Lozano R, Macín Pérez G, Gómez-Valdés J, Villamil-Ramírez H, Hunemeier T, Ramallo V, Silva de Cerqueira CC, Hurtado M, Villegas V, Granja V, Gallo C, Poletti G, Schuler-Faccini L, Salzano FM, Bortolini MC, Canizales-Quinteros S, Rothhammer F, Bedoya G, Gonzalez-José R, Headon D, López-Otín C, Tobin DJ, Balding D, Ruiz-Linares A. March 2016. A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features. Nature Communications. 7. 10815. 10.1038/ncomms10815. 4773514. 26926045. 2016NatCo...710815A.
12. Dipietromaria A, Benayoun BA, Todeschini AL, Rivals I, Bazin C, Veitia RA . Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems . Human Molecular Genetics . 18 . 17 . 3324–33 . September 2009 . 19515849 . 10.1093/hmg/ddp273 . 10.1.1.615.6877 .
13. Todeschini AL, Dipietromaria A, L'hôte D, Boucham FZ, Georges AB, Pandaranayaka PJ, Krishnaswamy S, Rivals I, Bazin C, Veitia RA . 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 . 21632871 . 10.1093/hmg/ddr244 . free .
14. Governini L, Carrarelli P, Rocha AL, Leo VD, Luddi A, Arcuri F, Piomboni P, Chapron C, Bilezikjian LM, Petraglia F . FOXL2 in human endometrium: hyperexpressed in endometriosis . en . Reproductive Sciences . 21 . 10 . 1249–55 . October 2014 . 24520083 . 10.1177/1933719114522549 . 25004354 .
15. Jin H, Won M, Park SE, Lee S, Park M, Bae J . 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 . 27414805 . 4944948 . 10.1371/journal.pone.0159112 . 2016PLoSO..1159112J . free .
16. Schmidt D, Ovitt CE, Anlag K, Fehsenfeld S, Gredsted L, Treier AC, Treier M . The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance . en . Development . 131 . 4 . 933–42 . February 2004 . 14736745 . 10.1242/dev.00969 . 31658647 . free .