Gadd45g Is Essential for Primary Sex Determination, Male Fertility and Testis Development

Abstract

In humans and most mammals, differentiation of the embryonic gonad into ovaries or testes is controlled by the Y-linked gene SRY. Here we show a role for the Gadd45g protein in this primary sex differentiation. We characterized mice deficient in Gadd45a, Gadd45b and Gadd45g, as well as double-knockout mice for Gadd45ab, Gadd45ag and Gadd45bg, and found a specific role for Gadd45g in male fertility and testis development. Gadd45g-deficient XY mice on a mixed 129/C57BL/6 background showed varying degrees of disorders of sexual development (DSD), ranging from male infertility to an intersex phenotype or complete gonadal dysgenesis (CGD). On a pure C57BL/6 (B6) background, all Gadd45g−/− XY mice were born as completely sex-reversed XY-females, whereas lack of Gadd45a and/or Gadd45b did not affect primary sex determination or testis development. Gadd45g expression was similar in female and male embryonic gonads, and peaked around the time of sex differentiation at 11.5 days post-coitum (dpc). The molecular cause of the sex reversal was the failure of Gadd45g−/− XY gonads to achieve the SRY expression threshold necessary for testes differentiation, resulting in ovary and Müllerian duct development. These results identify Gadd45g as a candidate gene for male infertility and 46,XY sex reversal in humans.

Gadd45 in Stress Signaling, Cell Cycle Control, and Apoptosis

“…A specifi c role was recently identifi ed for Gadd45g in gonad development, male fertility, and sex determination (Gierl et al 2012 ;Warr et al 2012 ;Johnen et al 2013 ). Notably, mice defi cient in Gadd45g show an unexpected male-to-female sex reversal phenotype.…”

“…Notably, mice defi cient in Gadd45g show an unexpected male-to-female sex reversal phenotype. Gadd45g-defi cient XY mice on a mixed 129/C57BL/6 background have varying degrees of disorders of sexual development, ranging from male infertility to complete gonadal dysgenesis (Johnen et al 2013 ). On a pure C57BL/6 background, all Gadd45g −/− XY mice were born as completely sex-reversed XY-females (Gierl et al 2012 ;Warr et al 2012 ;Johnen et al 2013 ).…”

“…Gadd45a and Gadd45b are not expressed in purifi ed somatic supporting precursor cells. Only Gadd45g expression is induced robustly in embryonic gonads and in somatic precursor cells (Johnen et al 2013 ).…”

“…Surprisingly, Gadd45g but not Gadd45a or Gadd45b is necessary for activation of the male sexdetermining pathway in mice and its absence leads to development of female gonads. Lack of Gadd45g decreases SRY expression and blocks SOX9 expression resulting in ovary and Müllerian duct development, whereas lack of Gadd45a and/ or Gadd45b has no effect on testis development (Johnen et al 2013 ). Although it remains to be determined how Gadd45g regulates SRY expression, it is proposed that Gadd45g is needed to promote MAP3K4-mediated activation of p38 signaling in murine embryonic gonadal somatic cells.…”

Switching on sex: transcriptional regulation of the testis-determining geneSry

“…Gadd45g is required for normal Sry expression (Gierl et al, 2012) and its loss leads to sex reversal (Johnen et al, 2013;. Importantly, Gadd45g expression in mice proceeds in a centre-to-pole wave that foreshadows the expression of Sry by ∼5 h .…”