Université Côte d’Azur, CNRS, Inserm, iBV, Nice, France
Sameh A Youssef
Department of Pathobiology, Dutch Molecular Pathology Center, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands; Department Pediatrics, Divisions Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
Department of Biology, Faculty of Science, Division of Developmental Biology, Reproductive Biology Group, Utrecht University, Utrecht, Netherlands
Alain de Bruin
Department of Pathobiology, Dutch Molecular Pathology Center, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands; Department Pediatrics, Divisions Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
Marie-Cécile De Cian
Université Côte d’Azur, CNRS, Inserm, iBV, Nice, France
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 RSPO1/Rspo1 in XX humans and mice leads to testicular differentiation and female-to-male sex reversal in a manner that does not requireSry or Sox9 in mice. Here we show that an alternate testis-differentiating factor exists and that this factor is Sox8. Specifically, genetic ablation of Sox8 and Sox9 prevents ovarian-to-testicular reprogramming observed in XX Rspo1 loss-of-function mice. Consequently, Rspo1 Sox8 Sox9 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.