Abstract
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 Rspo1KOSox9cKO ), 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 Rspo1KOSox9cKO mice. Moreover, since testis development occurs in XY Rspo1KOSox9cKO mice, our data show that Rspo1 is the main effector for male-to-female sex reversal in XY Sox9cKO 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.
Highlights
Mammalian sex determination depends on the primary developmental decision of the gonad to differentiate as testis or ovary
In XX individuals, Rspo1 is important for ovarian development as evidenced by female-to-male sex reversal of XX Rspo1 mutants
Since testicular differentiation appears concomitantly with Sox9 expression, it was assumed that Sox9 is the inducer of testicular differentiation in XX Rspo1 mutants
Summary
Mammalian sex determination depends on the primary developmental decision of the gonad to differentiate as testis or ovary. Loss-of-function mutations [6,7,15,16] and gain-of-function mutations [4,17,18] of Sry and Sox have been generated in mouse models, showing that Sry and Sox are necessary and sufficient to induce testis differentiation and the associated male development. Ablation of Rspo in mice yields female-to-male sex reversal and promotes Sox up-regulation correlated with differentiation of Sertoli cells and formation of testis cords at birth [20]. This gonadal dysgenesis yields development of an ovotestis, a gonad displaying both testicular and ovarian regions [20,21]. When the canonical beta-catenin signaling pathway is activated in XY gonads, this induces male-to-female sex reversal
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