Testicular Differentiation Occurs in Absence of R-spondin1 and Sox9 in Mouse Sex Reversals

• DOI: 10.1371/journal.pgen.1003170
• Publication Date: 2012-12-27T23:58:22Z
• Authors: Rowena Lavery; Anne-Amandine Cha...; Eva Pauper; Elodie P. Gregoire; Muriel Klopfenstein; Dirk G. de Rooij; Manuel Mark; Andreas Schedl; Norbert B. Ghysel...; Marie-Christine C...
• Keywords: Male; 0301 basic medicine; Sex Differentiation; Ovary; Gene Expression Regulation, Developmental; Cell Differentiation; SOX9 Transcription Factor; QH426-470; Sex Determination Processes; Mice; 03 medical and health sciences; Testis; Genetics; Animals; Humans; Female; Genes, sry; Thrombospondins; [SDV.BDD]Life Sciences [q-bio]/Development Biology; Wnt Signaling Pathway; Research Article; Signal Transduction

In mammals, male sex determination is governed by SRY-dependent activation of Sox9, whereas female development involves R-spondin1 (RSPO1), an activator of the WNT/beta-catenin signaling pathway. Genetic analyses in mice have demonstrated Sry and Sox9 to be both required and sufficient to induce testicular development. These genes are therefore considered as master regulators of the male pathway. Indeed, female-to-male sex reversal in XX Rspo1 mutant mice correlates with Sox9 expression, suggesting that this transcription factor induces testicular differentiation in pathological conditions. Unexpectedly, here we show that testicular differentiation can occur in XX mutants lacking both Rspo1 and Sox9 (referred to as XX Rspo1(KO)Sox9(cKO) ()), indicating that Sry and Sox9 are dispensable to induce female-to-male sex reversal. Molecular analyses show expression of both Sox8 and Sox10, suggesting that activation of Sox genes other than Sox9 can induce male differentiation in Rspo1(KO)Sox9(cKO) mice. Moreover, since testis development occurs in XY Rspo1(KO)Sox9(cKO) mice, our data show that Rspo1 is the main effector for male-to-female sex reversal in XY Sox9(cKO) mice. Thus, Rspo1 is an essential activator of ovarian development not only in normal situations, but also in sex reversal situations. Taken together these data demonstrate that both male and female sex differentiation is induced by distinct, active, genetic pathways. The dogma that considers female differentiation as a default pathway therefore needs to be definitively revised.