GADD45G Functions in Male Sex Determination by Promoting p38 Signaling and Sry Expression

Male sex determination in mammals is induced by Sry, a gene whose regulation is poorly understood. Here we show that mice mutant for the stress-response gene Gadd45g display complete male-to-female sex reversal. Gadd45g and Sty have a strikingly similar expression pattern in the genital ridge, and they are coexpressed in gonadal somatic cells. In Gadd45g mutants, Sty expression is delayed and reduced, and yet Sty seemed to remain poised for expression, because its promoter is demethylated on schedule and is occupied by active histone marks. Instead, p38 MAPK signaling is impaired in Gadd45g mutants. Moreover, the transcription factor GATA4, which is required for Sty expression, binds to the Sty promoter in vivo in a MAPK-dependent manner. The results suggest that a signaling cascade, involving GADD45G -> p38 MAPK -> GATA4 -> SRY, regulates male sex determination.