FOXL2 is a forkheadtranscription factor. The protein contains a fork-head DNA-binding domain and plays a role in ovarian development and function.[2] 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.[3]
In postnatal ovaries FOXL2 regulates granulosa cell differentiation and also supports the growth of the pre-ovulatory follicles during adult life.[4]
Regulation
FOXL2 has several post-translational modifications that modulate its stability, subcellular localization and pro-apoptotic activity.[5]
By a yeast-two-hybrid screening, 10 novel protein partners of FOXL2 are 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.[6]
Clinical significance
Sex determination
This protein is involved in sex determination. Female missing the FOXL2 gene appear male. FOXL2 knockout in mature mouse ovaries cause them to develop into testes, however oocytes are still formed.[7]
Mutations in this gene are a cause of blepharophimosis syndrome and/or premature ovarian failure 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 has been founded.[8]
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.[9]
Adult Granulosa Cell Tumors AGCT
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.[4]
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.[10]
Others 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.[11]
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[12]
↑ 4.04.1Leung DT, Fuller PJ, Chu S (March 2016). "Impact of FOXL2 mutations on signaling in ovarian granulosa cell tumors". The International Journal of Biochemistry & Cell Biology. 72: 51–4. doi:10.1016/j.biocel.2016.01.003. PMID26791928.
↑L'Hôte D, Georges A, Todeschini AL, Kim JH, Benayoun BA, Bae J, Veitia RA (July 2012). "Discovery of novel protein partners of the transcription factor FOXL2 provides insights into its physiopathological roles". Human Molecular Genetics. 21 (14): 3264–74. doi:10.1093/hmg/dds170. PMID22544055.
↑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 (December 2009). "Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation". Cell. 139 (6): 1130–42. doi:10.1016/j.cell.2009.11.021. PMID20005806. Lay summary – Nature News.
↑Dipietromaria A, Benayoun BA, Todeschini AL, Rivals I, Bazin C, Veitia RA (September 2009). "Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems". Human Molecular Genetics. 18 (17): 3324–33. doi:10.1093/hmg/ddp273. PMID19515849.
↑Todeschini AL, Dipietromaria A, L'hôte D, Boucham FZ, Georges AB, Pandaranayaka PJ, Krishnaswamy S, Rivals I, Bazin C, Veitia RA (September 2011). "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. doi:10.1093/hmg/ddr244. PMID21632871.
↑Governini L, Carrarelli P, Rocha AL, Leo VD, Luddi A, Arcuri F, Piomboni P, Chapron C, Bilezikjian LM, Petraglia F (October 2014). "FOXL2 in human endometrium: hyperexpressed in endometriosis". Reproductive Sciences. 21 (10): 1249–55. doi:10.1177/1933719114522549. PMID24520083.
↑Schmidt D, Ovitt CE, Anlag K, Fehsenfeld S, Gredsted L, Treier AC, Treier M (February 2004). "The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance". Development. 131 (4): 933–42. doi:10.1242/dev.00969. PMID14736745.
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 (February 1999). "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. doi:10.1006/geno.1998.5691. PMID10036183.
Kaestner KH, Knochel W, Martinez DE (January 2000). "Unified nomenclature for the winged helix/forkhead transcription factors". Genes & Development. 14 (2): 142–6. doi:10.1101/gad.14.2.142. PMID10702024.
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 (February 2001). "The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome". Nature Genetics. 27 (2): 159–66. doi:10.1038/84781. PMID11175783.
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 (July 2001). "Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation". Human Molecular Genetics. 10 (15): 1591–600. doi:10.1093/hmg/10.15.1591. PMID11468277.
Yamada T, Hayasaka S, Matsumoto M, Esa T, Hayasaka Y, Endo M (2002). "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. doi:10.1007/s100380170009. PMID11776388.
Kosaki K, Ogata T, Kosaki R, Sato S, Matsuo N (March 2002). "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. doi:10.1076/opge.23.1.43.2202. PMID11910558.
Bell R, Murday VA, Patton MA, Jeffery S (2002). "Two families with blepharophimosis/ptosis/epicanthus inversus syndrome have mutations in the putative forkhead transcription factor FOXL2". Genetic Testing. 5 (4): 335–8. doi:10.1089/109065701753617499. PMID11960581.
Harris SE, Chand AL, Winship IM, Gersak K, Aittomäki K, Shelling AN (August 2002). "Identification of novel mutations in FOXL2 associated with premature ovarian failure". Molecular Human Reproduction. 8 (8): 729–33. doi:10.1093/molehr/8.8.729. PMID12149404.
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 (November 2002). "Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families". American Journal of Medical Genetics. 113 (1): 47–51. doi:10.1002/ajmg.10741. PMID12400065.
Mazumdar A, Kumar R (January 2003). "Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells". FEBS Letters. 535 (1–3): 6–10. doi:10.1016/S0014-5793(02)03846-2. PMID12560069.
Fokstuen S, Antonarakis SE, Blouin JL (March 2003). "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. doi:10.1002/ajmg.a.10024. PMID12567411.
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 (February 2003). "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. doi:10.1034/j.1399-0004.2003.00011.x. PMID12630957.
Udar N, Yellore V, Chalukya M, Yelchits S, Silva-Garcia R, Small K (September 2003). "Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients". Human Mutation. 22 (3): 222–8. doi:10.1002/humu.10251. PMID12938087.
Crisponi L, Uda M, Deiana M, Loi A, Nagaraja R, Chiappe F, Schlessinger D, Cao A, Pilia G (May 2004). "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. doi:10.1016/j.ygeno.2003.11.010. PMID15081106.
L'Hôte D, Georges A, Todeschini AL, Kim JH, Benayoun BA, Bae J, Veitia RA (July 2012). "Discovery of novel protein partners of the transcription factor FOXL2 provides insights into its physiopathological roles". Human Molecular Genetics. 21 (14): 3264–74. doi:10.1093/hmg/dds170. PMID22544055.
Elzaiat M, Todeschini AL, Caburet S, Veitia RA (February 2017). "The genetic make-up of ovarian development and function: the focus on the transcription factor FOXL2". Clinical Genetics. 91 (2): 173–182. doi:10.1111/cge.12862. PMID27604691.