title: Disruption of mitotic arrest precedes precocious differentiation and transdifferentiation of pregranulosa cells in the perinatal Wnt4 mutant ovary.
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.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Maatouk
authors.forename: Lindsey
authors.initials: L
authors.lastname: Mork
authors.forename: Anne-Amandine
authors.initials: AA
authors.lastname: Chassot
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Chaboissier
authors.forename: Blanche
authors.initials: B
authors.lastname: Capel
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D054304:Anti-Mullerian Hormone / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D016923:Cell Death; D002454:Cell Differentiation; D054338:Cell Transdifferentiation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D006107:Granulosa Cells / Q000166:cytology* / Q000378:metabolism; D008297:Male; D008540:Meiosis; D051379:Mice; D008938:Mitosis; D009154:Mutation / Q000235:genetics*; D012708:Sertoli Cells / Q000166:cytology / Q000378:metabolism; D019699:Thrombospondins / Q000378:metabolism; D060528:Wnt4 Protein / Q000378:metabolism*
chemical_list: D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse; C518903:RSPO1 protein, mouse; D019699:Thrombospondins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D054304:Anti-Mullerian Hormone
keywords: Meiotic germ cells; Ovary; Rspo1; Sex determination; Sox9; Wnt4
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