title: R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation.
abstract: Sex differentiation is a unique developmental process. Starting from a bipotential gonad, it gives rise to the ovary and the testis, two highly specialized organs that differ morphologically and physiologically despite sharing common reproductive and endocrine functions. This highlights the specific plasticity of the gonadal precursors and the existence of complex antagonistic genetic regulation. Mammalian sex determination is controlled by paternal transmission of the Y-linked gene, sex-determining region Y (SRY). Using mouse models, it has been shown that the main role of Sry is to activate the expression of the transcription factor Sox9; either one of these two genes is necessary and sufficient to allow testicular development through Sertoli cell differentiation. Thus, defects in SRY/Sry and/or SOX9/Sox9 expression result in male-to-female sex reversal of XY individuals. Molecular mechanisms governing ovarian differentiation remained unknown for a long time, until the discovery of the roles of R-spondin1 (RSPO1) and WNT4. In XX individuals, activation of the β-catenin signaling pathway by the secreted proteins RSPO1 and WNT4 is required to allow granulosa cell differentiation and, in turn, ovarian differentiation. Thus, mutations in RSPO1 result in female-to-male sex reversal of XX patients, and mouse models have allowed the identification of genetic cascades activated by RSPO1 and WNT4 to regulate ovarian development. In this review, we will discuss the respective roles of RSPO1, WNT4, and the β-catenin signaling pathway during ovarian differentiation in mice.
authors.affiliation: University of Nice-Sophia AntipolisParc Valrose, F-06108 Nice, FranceUMR-INSERM1091IBV, F-06108 Nice, France University of Nice-Sophia AntipolisParc Valrose, F-06108 Nice, FranceUMR-INSERM1091IBV, F-06108 Nice, France chassot@unice.fr marie-christine.chaboissier@unice.fr.
authors.forename: Anne-Amandine
authors.initials: AA
authors.lastname: Chassot
authors.affiliation: University of Nice-Sophia AntipolisParc Valrose, F-06108 Nice, FranceUMR-INSERM1091IBV, F-06108 Nice, France University of Nice-Sophia AntipolisParc Valrose, F-06108 Nice, FranceUMR-INSERM1091IBV, F-06108 Nice, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gillot
authors.affiliation: University of Nice-Sophia AntipolisParc Valrose, F-06108 Nice, FranceUMR-INSERM1091IBV, F-06108 Nice, France University of Nice-Sophia AntipolisParc Valrose, F-06108 Nice, FranceUMR-INSERM1091IBV, F-06108 Nice, France chassot@unice.fr marie-christine.chaboissier@unice.fr.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Chaboissier
mesh_terms: D058531:46, XX Testicular Disorders of Sex Development / Q000503:physiopathology; D000818:Animals; D005075:Biological Evolution; D002454:Cell Differentiation / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D005854:Germ Cells / Q000166:cytology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009024:Morphogenesis / Q000502:physiology*; D010053:Ovary / Q000166:cytology*; D019849:Sex Determination Processes / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D019699:Thrombospondins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D060528:Wnt4 Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: C495267:CTNNB1 protein, mouse; C518903:RSPO1 protein, mouse; D019699:Thrombospondins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D051176:beta Catenin