Figure 7.

Summary of Proposed Interactions between GADD45γ, MAP3K4, p38 MAPK, GATA4, and Sry in Testis Determination

The signals regulating the expression of Gadd45γ shortly after gonad formation (indicated by a question mark at the top) are unknown. Based on data reported here and described in the supporting literature, we propose that GADD45γ activates MAP3K4 in supporting cell precursors of the developing gonad from around 10.5 dpc. MAP3K4 activates p38α and p38β (indicated by a circled P) through an as yet uncharacterized MAP2K. This MAPK phosphorelay module, perhaps in the context of an unidentified scaffold protein, results in the direct or indirect activation of GATA4 by phosphorylation (dashed arrow) and subsequent expression of Sry in XY supporting cells. In addition to DNA demethylation of its promoter region (white circles on DNA strand), which does not require GADD45γ/MAP3K4, timely Sry expression may require chromatin marks also established by this signal transduction pathway (green circles). Additional targets of this MAPK cascade in the developing gonad are not excluded but remain to be identified, possibly comprising other chromatin-associated transcription factors (TFs), transcriptional cofactors, and chromatin-modifying enzymes that alter chromatin configuration at Sry (and/or other loci).