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

Nainoa Richardson,Marie-Cécile De Cian,Elodie P Gregoire,Isabelle Gillot,Marie-Christine Chaboissier,Sameh A Youssef,Alain De Bruin,Dirk De Rooij

doi:10.7554/elife.53972

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 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.

Highlights

During primary sex determination in mammals, a common precursor organ, the bipotential gonad, develops as a testis or ovary
We chose to study embryonic day 17.5 (E17.5) fetal gonads, when testis cords form in Rspo1 sex reversal mice, and juvenile postnatal day 10 (P10) gonads, when gonadal fate is likely to be set (Lavery et al, 2012)
In XY gonads, Rspo1 is mostly localized to the coelomic epithelium at E17.5 and to the tunica albuginea at P10 (Figure 1 Aa, c)

Summary

Introduction

During primary sex determination in mammals, a common precursor organ, the bipotential gonad, develops as a testis or ovary. Testicular development begins when SRY and SOX9 are expressed in the bipotential XY gonad. These transcription factors promote supporting cell progenitors to differentiate as Sertoli cells and form sex cords (Gonen et al, 2018; Chaboissier et al, 2004; Barrionuevo et al, 2006), and this triggers a cascade of signaling events that are required for the differentiation of other cell populations in the testis (Koopman et al, 1991; Vidal et al, 2001). Inappropriate regulation within the molecular pathways governing sex determination can lead to partial or complete sex reversal phenotypes and infertility (Wilhelm et al, 2009)

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Results

Conclusion