Fertility and Sterility
Volume 94, Issue 1 , Pages 353-356 , June 2010

Human forkhead L2 represses key genes in granulosa cell differentiation including aromatase, P450scc, and cyclin D2

  • Ikuko K. Bentsi-Barnes, Ph.D.

      Affiliations

    • Division of Reproductive Endocrinology and Infertility, Department of Obstetrics/Gynecology, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Fang-Ting Kuo, Ph.D.

      Affiliations

    • Division of Reproductive Endocrinology and Infertility, Department of Obstetrics/Gynecology, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Gillian M. Barlow, Ph.D.

      Affiliations

    • Division of Reproductive Endocrinology and Infertility, Department of Obstetrics/Gynecology, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Margareta D. Pisarska, M.D.

      Affiliations

    • Division of Reproductive Endocrinology and Infertility, Department of Obstetrics/Gynecology, Cedars-Sinai Medical Center, Los Angeles, California
    • David Geffen School of Medicine, UCLA, Los Angeles, California
    • Corresponding Author InformationReprint requests: Margareta D. Pisarska, M.D., Center of Fertility and Reproductive Medicine, Division of REI, Department of Ob/Gyn, Cedars-Sinai Medical Center, 8635 West Third Street, Suite 160W, Los Angeles, CA 90048 (FAX: 310-423-0140).

Received 29 May 2009 ,Revised 15 September 2009 ,Accepted 23 September 2009.

References 

  1. McGee EA, Hsueh AJ. Initial and cyclic recruitment of ovarian follicles. Endocrinol Rev. 2000;21:200–214
  2. Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol. 1986;67:604–606
  3. Fassnacht W, Mempel A, Strowitzki T, Vogt PH. Premature ovarian failure (POF) syndrome: towards the molecular clinical analysis of its genetic complexity. Curr Med Chem. 2006;13:1397–1410
  4. Schlessinger D, Herrera L, Crisponi L, Mumm S, Percesepe A, Pellegrini M, et al. Genes and translocations involved in POF. Am J Med Genet. 2002;111:328–333
  5. De Baere E, BD, Oley C, Lorenz B, Cocquet J, De Sutter P, Devriendt K, et al. FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. Am J Hum Genet 2003;72:478–487.
  6. Fuhrer D. Lessons from studies of complex genetic disorders: identification of FOXL2—a novel transcription factor on the wing to fertility. Eur J Endocrinol. 2002;146:15–18
  7. Kaufmann E, Knochel W. Five years on the wings of fork head. Mech Dev. 1996;57:3–20
  8. Schmidt D, Ovitt CE, Anlag K, Fehsenfeld S, Gredsted L, Treier AC, et al. The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development. 2004;131:933–942
  9. Uda M, Ottolenghi C, Crisponi L, Garcia JE, Deiana M, Kimber W, et al. Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development. Hum Mol Genet. 2004;13:1171–1181
  10. De Baere E, Dixon MJ, Small KW, Jabs EW, Leroy BP, Devriendt K, et al. Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype–phenotype correlation. Hum Mol Genet. 2001;10:1591–1600
  11. Pisarska MD, Bae J, Klein C, Hsueh AJ. Forkhead l2 is expressed in the ovary and represses the promoter activity of the steroidogenic acute regulatory gene. Endocrinology. 2004;145:3424–3433
  12. Pollack SE, Furth EE, Kallen CB, Arakane F, Kiriakidou M, Kozarsky KF, et al. Localization of the steroidogenic acute regulatory protein in human tissues. J Clin Endocrinol Metab. 1997;82:4243–4251
  13. Stocco C. Aromatase expression in the ovary: hormonal and molecular regulation. Steroids. 2008;73:473–487
  14. Stocco DM. Intramitochondrial cholesterol transfer. Biochim Biophys Acta. 2000;1486:184–197
  15. Moons DS, Jirawatnotai S, Tsutsui T, Franks R, Parlow AF, Hales DB, et al. Intact follicular maturation and defective luteal function in mice deficient for cyclin- dependent kinase-4. Endocrinology. 2002;143:647–654
  16. Huang Y, Ohtani K, Iwanaga R, Matsumura Y, Nakamura M. Direct trans-activation of the human cyclin D2 gene by the oncogene product Tax of human T-cell leukemia virus type I. Oncogene. 2001;20:1094–1102
  17. Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet. 2001;27:159–166
  18. Suzuki T, Sasano H, Tamura M, Aoki H, Fukaya T, Yajima A, et al. Temporal and spatial localization of steroidogenic enzymes in premenopausal human ovaries: in situ hybridization and immunohistochemical study. Mol Cell Endocrinol. 1993;97:135–143
  19. Robker RL, Richards JS. Hormone-induced proliferation and differentiation of granulosa cells: a coordinated balance of the cell cycle regulators cyclin D2 and p27Kip1. Mol Endocrinol. 1998;12:924–940
  20. Nakae J, Kitamura T, Kitamura Y, Biggs WH, Arden KC, Accili D. The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev Cell. 2003;4:119–129
  21. Brissette JL, Li J, Kamimura J, Lee D, Dotto GP. The product of the mouse nude locus, Whn, regulates the balance between epithelial cell growth and differentiation. Genes & Dev. 1996;10:2212–2221
  22. Blixt A, Mahlapuu M, Aitola M, Pelto-Huikko M, Enerback S, Carlsson P. A forkhead gene, FoxE3, is essential for lens epithelial proliferation and closure of the lens vesicle. Genes & Dev. 2000;14:245–254
  23. Zhou L, Dey CR, Wert SE, Yan C, Costa RH, Whitsett JA. Hepatocyte nuclear factor-3beta limits cellular diversity in the developing respiratory epithelium and alters lung morphogenesis in vivo. Dev Dyn. 1997;210:305–314
  24. Liu Z, Rudd MD, Hernandez-Gonzalez I, Gonzalez-Robayna I, Fan HY, Zeleznik AJ, et al. FSH and FOXO1 regulate genes in the sterol/steroid and lipid biosynthetic pathways in granulosa cells. Mol Endocrinol. 2009;23:649–661
  25. Benayoun BA, Caburet S, Dipietromaria A, Bailly-Bechet M, Batista F, Fellous M, et al. The identification and characterization of a FOXL2 response element provides insights into the pathogenesis of mutant alleles. Hum Mol Genet. 2008;17:3118–3127
  26. Kuo FT, Bentsi-Barnes IK, Barlow GM, Bae J, Pisarska MD. Sumoylation of Forkhead L2 by Ubc9 is required for its activity as a transcriptional repressor of the Steroidogenic Acute Regulatory gene. Cell Signal. 2009;
  27. Benayoun BA, Batista F, Auer J, Dipietromaria A, L'Hote D, De Baere E, et al. Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations. Hum Mol Genet. 2009;18:632–644
  28. Johnson ES. Protein modification by SUMO. Ann Rev Biochem. 2004;73:355–382
  29. Oshima Y, Uno Y, Matsuda Y, Kobayashi T, Nakamura M. Molecular cloning and gene expression of Foxl2 in the frog Rana rugosa. Gen Comp Endocrinol. 2008;159:170–177
  30. Nakamoto M, Wang DS, Suzuki A, Matsuda M, Nagahama Y, Shibata N. Dax1 suppresses P450arom expression in medaka ovarian follicles. Mol Reprod Dev. 2007;74:1239–1246
  31. Wang DS, Kobayashi T, Zhou LY, Paul-Prasanth B, Ijiri S, Sakai F, et al. Foxl2 up-regulates aromatase gene transcription in a female-specific manner by binding to the promoter as well as interacting with ad4 binding protein/steroidogenic factor 1. Mol Endocrinol. 2007;21:712–725
  32. Yamaguchi T, Yamaguchi S, Hirai T, Kitano T. Follicle-stimulating hormone signaling and Foxl2 are involved in transcriptional regulation of aromatase gene during gonadal sex differentiation in Japanese flounder, Paralichthys olivaceus. Biochem Biophys Res Commun. 2007;359:935–940

 I.K.B.-B. has nothing to disclose. F.-T.K. has nothing to disclose. G.M.B. has nothing to disclose. M.D.P. has nothing to disclose.

 Supported by grant R01HD047603 from the National Institute of Child Health and Human Development and the Office of Research on Women's Health, Bethesda, Maryland (M.D.P.) and by a grant from the Helping Hands of Los Angeles, Inc., Los Angeles, California (M.D.P.).

PII: S0015-0282(09)03800-X

doi: 10.1016/j.fertnstert.2009.09.050

Fertility and Sterility
Volume 94, Issue 1 , Pages 353-356 , June 2010

Article Tools

* Image Usage & Resolution