Gadd45γ and Map3k4 Interactions Regulate Mouse Testis Determination via p38 MAPK-Mediated Control of Sry Expression

Loss of the kinase MAP3K4 causes mouse embryonic gonadal sex reversal due to reduced expression of the testis-determining gene, Sty. However, because of widespread expression of MAP3K4, the cellular basis of this misregulation was unclear. Here, we show that mice lacking Gadd45 gamma also exhibit XY gonadal sex reversal caused by disruption to Sty expression. Gadd45 gamma is expressed in a dynamic fashion in somatic cells of the developing gonads from 10.5 days postcoitum (dpc) to 12.5 dpc. Gadd45 gamma and Map3k4 genetically interact during sex determination, and transgenic overexpression of Map3k4 rescues gonadal defects in Gadd45 gamma-deficient embryos. Sex reversal in both mutants is associated with reduced phosphorylation of p38 MAPK and GATA4. In addition, embryos lacking both p380 alpha and p38 beta also exhibit XY gonadal sex reversal. Taken together, our data suggest a requirement for GADD45 gamma in promoting MAP3K4-mediated activation of p38 MAPK signaling in embryonic gonadal somatic cells for testis determination in the mouse.