Disruption of Mitotic Arrest Precedes Precocious Differentiation and Transdifferentiation of Pregranulosa Cells in the Perinatal Wnt4 Mutant Ovary

Overview

Journal Dev Biol

Publisher Elsevier

Specialties Biology
Reproductive Medicine

Date 2013 Sep 17

PMID 24036309

Citations 26

Authors

Danielle M Maatouk

Lindsey Mork

Anne-Amandine Chassot

Marie-Christine Chaboissier

Blanche Capel

Affiliations

Soon will be listed here.

Abstract

Mammalian sex determination is controlled by antagonistic pathways that are initially co-expressed in the bipotential gonad and subsequently become male- or female-specific. In XY gonads, testis development is initiated by upregulation of Sox9 by SRY in pre-Sertoli cells. Disruption of either gene leads to complete male-to-female sex reversal. Ovarian development is dependent on canonical Wnt signaling through Wnt4, Rspo1 and β-catenin. However, only a partial female-to-male sex reversal results from disruption of these ovary-promoting genes. In Wnt4 and Rspo1 mutants, there is evidence of pregranulosa cell-to-Sertoli cell transdifferentiation near birth, following a severe decline in germ cells. It is currently unclear why primary sex reversal does not occur at the sex-determining stage, but instead occurs near birth in these mutants. Here we show that Wnt4-null and Rspo1-null pregranulosa cells transition through a differentiated granulosa cell state prior to transdifferentiating towards a Sertoli cell fate. This transition is preceded by a wave of germ cell death that is closely associated with the disruption of pregranulosa cell quiescence. Our results suggest that maintenance of mitotic arrest in pregranulosa cells may preclude upregulation of Sox9 in cases where female sex-determining genes are disrupted. This may explain the lack of complete sex reversal in such mutants at the sex-determining stage.

Citing Articles

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References

Menke D, Page D . Sexually dimorphic gene expression in the developing mouse gonad. Gene Expr Patterns. 2003; 2(3-4):359-67. DOI: 10.1016/s1567-133x(02)00022-4. View

RAYMOND C, Murphy M, OSullivan M, Bardwell V, Zarkower D . Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. Genes Dev. 2000; 14(20):2587-95. PMC: 316999. DOI: 10.1101/gad.834100. View

Schmidt D, Ovitt C, Anlag K, Fehsenfeld S, Gredsted L, Treier A . The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development. 2004; 131(4):933-42. DOI: 10.1242/dev.00969. View

Behringer R, Finegold M, Cate R . Müllerian-inhibiting substance function during mammalian sexual development. Cell. 1994; 79(3):415-25. DOI: 10.1016/0092-8674(94)90251-8. View

LITTLE C, CLOUDMAN A . The Occurrence of a Dominant Spotting Mutation in the House Mouse. Proc Natl Acad Sci U S A. 1937; 23(10):535-7. PMC: 1076983. DOI: 10.1073/pnas.23.10.535. View

Kim Y, Capel B . Balancing the bipotential gonad between alternative organ fates: a new perspective on an old problem. Dev Dyn. 2006; 235(9):2292-300. DOI: 10.1002/dvdy.20894. View

Colvin J, Green R, Schmahl J, Capel B, Ornitz D . Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell. 2001; 104(6):875-89. DOI: 10.1016/s0092-8674(01)00284-7. View

Hacker A, Capel B, Goodfellow P, Lovell-Badge R . Expression of Sry, the mouse sex determining gene. Development. 1995; 121(6):1603-14. DOI: 10.1242/dev.121.6.1603. View

Tomizuka K, Horikoshi K, Kitada R, Sugawara Y, Iba Y, Kojima A . R-spondin1 plays an essential role in ovarian development through positively regulating Wnt-4 signaling. Hum Mol Genet. 2008; 17(9):1278-91. DOI: 10.1093/hmg/ddn036. View

10.

Menke D, Koubova J, Page D . Sexual differentiation of germ cells in XX mouse gonads occurs in an anterior-to-posterior wave. Dev Biol. 2003; 262(2):303-12. DOI: 10.1016/s0012-1606(03)00391-9. View

11.

Yoshimizu T, Sugiyama N, De Felice M, Yeom Y, Ohbo K, Masuko K . Germline-specific expression of the Oct-4/green fluorescent protein (GFP) transgene in mice. Dev Growth Differ. 2000; 41(6):675-84. DOI: 10.1046/j.1440-169x.1999.00474.x. View

12.

Uhlenhaut N, Jakob S, Anlag K, Eisenberger T, Sekido R, Kress J . Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell. 2009; 139(6):1130-42. DOI: 10.1016/j.cell.2009.11.021. View

13.

Qin Y, Bishop C . Sox9 is sufficient for functional testis development producing fertile male mice in the absence of Sry. Hum Mol Genet. 2005; 14(9):1221-9. DOI: 10.1093/hmg/ddi133. View

14.

Tevosian S, Manuylov N . To beta or not to beta: canonical beta-catenin signaling pathway and ovarian development. Dev Dyn. 2008; 237(12):3672-80. PMC: 2837360. DOI: 10.1002/dvdy.21784. View

15.

Stallock J, Molyneaux K, Schaible K, Knudson C, Wylie C . The pro-apoptotic gene Bax is required for the death of ectopic primordial germ cells during their migration in the mouse embryo. Development. 2003; 130(26):6589-97. DOI: 10.1242/dev.00898. View

16.

Bullejos M, Koopman P . Spatially dynamic expression of Sry in mouse genital ridges. Dev Dyn. 2001; 221(2):201-5. DOI: 10.1002/dvdy.1134. View

17.

McLaren A . Meiosis and differentiation of mouse germ cells. Symp Soc Exp Biol. 1984; 38:7-23. View

18.

Ottolenghi C, Pelosi E, Tran J, Colombino M, Douglass E, Nedorezov T . Loss of Wnt4 and Foxl2 leads to female-to-male sex reversal extending to germ cells. Hum Mol Genet. 2007; 16(23):2795-804. DOI: 10.1093/hmg/ddm235. View

19.

Liu C, Liu C, Yao H . Building pathways for ovary organogenesis in the mouse embryo. Curr Top Dev Biol. 2010; 90:263-90. PMC: 3400115. DOI: 10.1016/S0070-2153(10)90007-0. View

20.

Bowles J, Knight D, Smith C, Wilhelm D, Richman J, Mamiya S . Retinoid signaling determines germ cell fate in mice. Science. 2006; 312(5773):596-600. DOI: 10.1126/science.1125691. View