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 b-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 b-catenin signaling pathway during ovarian differentiation in mice.Reproduction (2014) 148 R97-R110

Ex vivo cultures combined with vivo-morpholino induced gene knockdown provide a system to assess the role of WT1 and GATA4 during gonad differentiation

“…Our data suggest that GATA4 does not contribute to the sexually dimorphic expression of Ctnnb1 (Fig 4C and 4D), but rather sustains basal levels of β-catenin necessary for gonadal development in both, males and females [51]. FST is a secreted glycoprotein, which prevents the formation of testis-specific vasculature and germ cell death through inhibition of activin B [52,53].…”

Methylation Patterns of <b><i>SOX3, SOX9</i></b>, and <b><i>WNT4</i></b> Genes in Gonads of Dogs with XX (<b><i>SRY</i></b>-Negative) Disorder of Sexual Development

“…Therefore, hypomethylation of the SOX9 promoter in the studied dogs is not surprising. The WNT4 gene encodes a protein which, together with RSPO1, activates the β-catenin signaling pathway, essential for normal ovarian differentiation [Chassot et al, 2014]. Although WNT4 function is well defined [Chassot et al, 2014] and the organization of its promoter is known [Yu et al, 2009], there have been no previous The same superscripts in a row indicate significant differences between CpGs in the groups of dogs analyzed, A p < 0.01, a-f p < 0.…”

Characterization of β-catenin 1 during the gonad development in the common carp (Cyprinus carpio )

“…E2 is involved in promoting vitellogenesis and follicle growth during the early stages of ovarian development (Sharon & Glen, ). In mammals, the Foxl2‐leading oestrogen pathway acts in an independent and complementary manner with Rspo1/Wnt/β‐catenin signalling pathway to promote ovarian development (Chassot, Gillot & Chaboissier, ; Liu et al., ; Maatouk et al., ; Parma et al., ). Interestingly, serum E2 levels did not differ between the control and the β ‐catenin 1 deficient fish in O. niloticus (Wu et al., ).…”