| Summary: | The transcription factors SRY and SOX9 and RSPO1/WNT4/β-Catenin signaling act as antagonistic pathways to drive testis and ovary development respectively, from a common gonadal primordium in mouse embryos. In this work, we took advantage of a double knockout mouse model to study gonadal development when <i>Sox9</i> and <i>Wnt4</i> are both mutated. We show that the XX gonad mutant for <i>Wnt4</i> or for both <i>Wnt4</i> and <i>Sox9</i> develop as ovotestes, demonstrating that ectopic SOX9 function is not required for the partial female-to-male sex reversal caused by a <i>Wnt4</i> mutation. <i>Sox9</i> deletion in XY gonads leads to ovarian development accompanied by ectopic WNT/β-catenin signaling. In XY <i>Sox9</i> mutant gonads, SRY-positive supporting precursors adopt a female-like identity and develop as pre-granulosa-like cells. This phenotype cannot be fully prevented by the deletion of <i>Wnt4</i> or <i>Rspo1</i>, indicating that SOX9 is required for the early determination of the male supporting cell identity independently of repressing RSPO1/WNT4/β-Catenin signaling. However, in XY <i>Sox9 Wnt4</i> double mutant gonads, pre-granulosa cells are not maintained, as they prematurely differentiate as mature granulosa cells and then trans-differentiate into Sertoli-like cells. Together, our results reveal the dynamics of the specific and independent actions of SOX9 and WNT4 during gonadal differentiation: SOX9 is essential in the testis for early specification of male-supporting cells whereas WNT4 functions in the ovary to maintain female-supporting cell identity and inhibit male-specific vascular and steroidogenic cell differentiation.
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