R-spondin1 plays an essential role in ovarian development through positively regulating Wnt-4 signaling

Abstract

In mammals, female development has traditionally been considered a default process in the absence of the testis-determining gene, Sry. Recently, it has been documented that the gene for R-spondin1 (RSPO1), a novel class of soluble activator for Wnt/beta-catenin signaling, is mutated in two Italian families with female-to-male (XX) sex reversal. To elucidate the role of Rspo1 as a candidate female-determining gene in a mouse model, we generated Rspo1-null (Rspo1(-/-)) mice and found that Rspo1(-/-) XX mice displayed masculinized features including pseudohermaphroditism in genital ducts, depletion of fetal oocytes, male-specific coelomic vessel formation and ectopic testosterone production in the ovaries. Thus, although Rspo1 is required to fully suppress the male differentiation program and to maintain germ cell survival during the development of XX gonads, the loss of its activity has proved to be insufficient to cause complete XX sex reversal in mice. Interestingly, these partial sex-reversed phenotypes of Rspo1(-/-) XX mice recapitulated those of previously described Wnt-4(-/-) XX mice. In accordance with this finding, the expression of Wnt-4 and its downstream genes was deregulated in early Rspo1(-/-) XX gonads, suggesting that Rspo1 may participate in suppressing the male pathway in the absence of Sry and maintaining oocyte survival through positively regulating Wnt-4 signaling.

Secreted and Transmembrane Wnt Inhibitors and Activators

“…These mutations result either in a stop codon immediately after the signal peptide or in a truncated protein lacking the first furinlike domain, and thus are linked to the inability of Rspo1 to activate Wnt signaling. The potential role of Rspo1 as a candidate female-determining gene is confirmed in Rspo1 knockout XX mice, which display masculinized ovaries (ovotestis) with epididymis and vas deferens-like structures (Chassot et al 2008;Tomizuka et al 2008). The observed reduction of Wnt4 expression and the impaired Wnt/bcatenin activity in these mice, as well as the sex reversal phenotype observed in Wnt4 2/2 animals (Vainio et al 1999), suggest a crucial role for Rspo1/Wnt4/b-catenin signaling in ovary development.…”

R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation

“…However, RSPO1 can act as a potent specific mitogen by promoting the proliferation of intestinal cells (Kim et al 2005). During development, Rspo1 plays key roles in sex determination and ovarian differentiation (Chassot et al 2008a, Tomizuka et al 2008). Rspo1 has also been shown to be involved in mammary gland formation in mice and angiogenesis in zebrafish.…”

Changes in gonadal gene network by exogenous ligands in temperature-dependent sex determination

“…A transcription factor, sex-determining region on Y chromosome-box 9 (Sox9), a direct target of the transcription factor SRY during testicular differentiation in mammals, is upregulated at the MPT and downregulated at the FPT in embryonic gonads (Shoemaker et al 2007a). Accumulating evidences suggest that Rspo1 and Sox9 are balancing factors to determine a unidirectional result of gonad phenotype in mammals (Huang et al 1999, Barrionuevo et al 2006, Parma et al 2006, Chassot et al 2008, Tomizuka et al 2008. In this study, we examined the expression pattern of three candidate sex-determining genes in TSD, aromatase, Rspo1, and Sox9, in exogenous ligand-mediated sex determination in red-eared slider gonads.…”