<i>Sox8</i> and <i>Sox9</i> act redundantly for ovarian-to-testicular fate reprogramming in the absence of <i>R-spondin1</i> in mouse sex reversals.

Abstract

In mammals, testicular differentiation is initiated by transcription factors SRY and SOX9 in XY gonads, and ovarian differentiation involves R-spondin1 (RSPO1) mediated activation of WNT/β-catenin signaling in XX gonads. Accordingly, the absence of <i>RSPO1/Rspo1</i> in XX humans and mice leads to testicular differentiation and female-to-male sex reversal in a manner that does not require<i>Sry</i> or <i>Sox9</i> in mice. Here we show that an alternate testis-differentiating factor exists and that this factor is <i>Sox8</i>. Specifically, genetic ablation of <i>Sox8</i> and <i>Sox9</i> prevents ovarian-to-testicular reprogramming observed in XX <i>Rspo1</i> loss-of-function mice. Consequently, <i>Rspo1 Sox8 Sox9</i> triple mutant gonads developed as atrophied ovaries. Thus, SOX8 alone can compensate for the loss of SOX9 for Sertoli cell differentiation during female-to-male sex reversal.