The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance - PubMed

Affiliations

• PMID: 14736745
• DOI: 10.1242/dev.00969

The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance

Dirk Schmidt et al. Development. 2004 Feb.

Abstract

Human Blepharophimosis/ptosis/epicanthus inversus syndrome (BPES) type I is an autosomal dominant disorder associated with premature ovarian failure (POF) caused by mutations in FOXL2, a winged-helix/forkhead domain transcription factor. Although it has been shown that FOXL2 is expressed in adult ovaries, its function during folliculogenesis is not known. Here, we show that the murine Foxl2 gene is essential for granulosa cell differentiation and ovary maintenance. In Foxl2(lacZ) homozygous mutant ovaries granulosa cells do not complete the squamous to cuboidal transition leading to the absence of secondary follicles and oocyte atresia. We further demonstrate that activin-betaA and anti-Mullerian inhibiting hormone expression is absent or strongly diminished in Foxl2(lacZ) homozygous mutant ovaries. Unexpectedly, two weeks after birth most if not all oocytes expressed Gdf9 in Foxl2(lacZ) homozygous mutant ovaries, indicating that nearly all primordial follicles have already initiated folliculogenesis at this stage. This activation, in the absence of functional granulosa cells, leads to oocyte atresia and progressive follicular depletion. In addition to providing a molecular mechanism for premature ovarian failure in BPES, these results suggest that granulosa cell function is not only crucial for oocyte growth but also to maintain follicular quiescence in vivo.

Similar articles

• The human FOXL2 mutation database.

  Beysen D, Vandesompele J, Messiaen L, De Paepe A, De Baere E. Beysen D, et al. Hum Mutat. 2004 Sep;24(3):189-93. doi: 10.1002/humu.20079. Hum Mutat. 2004. PMID: 15300845

• Foxl2 function in ovarian development.

  Uhlenhaut NH, Treier M. Uhlenhaut NH, et al. Mol Genet Metab. 2006 Jul;88(3):225-34. doi: 10.1016/j.ymgme.2006.03.005. Epub 2006 May 2. Mol Genet Metab. 2006. PMID: 16647286 Review.

• Mutations in the coding region of the FOXL2 gene are not a major cause of idiopathic premature ovarian failure.

  Bodega B, Porta C, Crosignani PG, Ginelli E, Marozzi A. Bodega B, et al. Mol Hum Reprod. 2004 Aug;10(8):555-7. doi: 10.1093/molehr/gah078. Epub 2004 Jun 4. Mol Hum Reprod. 2004. PMID: 15181179

• Premature ovarian failure and forkhead transcription factor FOXL2: blepharophimosis-ptosis-epicanthus inversus syndrome and ovarian dysfunction.

  De Baere E, Copelli S, Caburet S, Laissue P, Beysen D, Christin-Maitre S, Bouchard P, Veitia R, Fellous M. De Baere E, et al. Pediatr Endocrinol Rev. 2005 Jun;2(4):653-60. Pediatr Endocrinol Rev. 2005. PMID: 16208278 Review.

• A novel insertion mutation in the FOXL2 gene is detected in a big Chinese family with blepharophimosis-ptosis-epicanthus inversus.

  Qian X, Shu A, Qin W, Xing Q, Gao J, Yang J, Feng G, He L. Qian X, et al. Mutat Res. 2004 Oct 4;554(1-2):19-22. doi: 10.1016/j.mrfmmm.2004.02.014. Mutat Res. 2004. PMID: 15450400

Cited by

• The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited.

  Rosenfield RL, Ehrmann DA. Rosenfield RL, et al. Endocr Rev. 2016 Oct;37(5):467-520. doi: 10.1210/er.2015-1104. Epub 2016 Jul 26. Endocr Rev. 2016. PMID: 27459230 Free PMC article. Review.

• Exposure to chemical cocktails before or after conception--- the effect of timing on ovarian development.

  Bellingham M, Amezaga MR, Mandon-Pepin B, Speers CJ, Kyle CE, Evans NP, Sharpe RM, Cotinot C, Rhind SM, Fowler PA. Bellingham M, et al. Mol Cell Endocrinol. 2013 Aug 25;376(1-2):156-72. doi: 10.1016/j.mce.2013.06.016. Epub 2013 Jun 20. Mol Cell Endocrinol. 2013. PMID: 23791816 Free PMC article.

• RUNX1 maintains the identity of the fetal ovary through an interplay with FOXL2.

  Nicol B, Grimm SA, Chalmel F, Lecluze E, Pannetier M, Pailhoux E, Dupin-De-Beyssat E, Guiguen Y, Capel B, Yao HH. Nicol B, et al. Nat Commun. 2019 Nov 11;10(1):5116. doi: 10.1038/s41467-019-13060-1. Nat Commun. 2019. PMID: 31712577 Free PMC article.

• Mechanisms of primordial follicle activation and new pregnancy opportunity for premature ovarian failure patients.

  Zhang T, He M, Zhang J, Tong Y, Chen T, Wang C, Pan W, Xiao Z. Zhang T, et al. Front Physiol. 2023 Feb 28;14:1113684. doi: 10.3389/fphys.2023.1113684. eCollection 2023. Front Physiol. 2023. PMID: 36926197 Free PMC article. Review.

• Synergistic activation of the Mc2r promoter by FOXL2 and NR5A1 in mice.

  Yang WH, Gutierrez NM, Wang L, Ellsworth BS, Wang CM. Yang WH, et al. Biol Reprod. 2010 Nov;83(5):842-51. doi: 10.1095/biolreprod.110.085621. Epub 2010 Jul 21. Biol Reprod. 2010. PMID: 20650879 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Silverchair Information Systems

• Other Literature Sources

  • The Lens - Patent Citations Database

• Molecular Biology Databases

  • BioCyc
  • Gene Ontology
  • Mouse Genome Informatics (MGI)