The Role of MAP3K1 in the Development of the Female Reproductive Tracts

Mitogen-Activated Protein 3 Kinase 1 (MAP3K1) is a dynamic signaling molecule with myriad cell-type specific functions not yet fully understood. Here we describe a role of MAP3K1 in the development of female reproductive tract (FRT). MAP3K1 kinase domain deficient females (Map3k1?KD) exhibit imperforate vagina, labor failure and sterility. The defects correspond to shunted Müllerian duct (MD), precursor of the FRT, in embryos, and contorted caudal vagina and abrogated vagina-urogenital sinus fusion in newborns. Although MAP3K1 acts through JNK and ERK to activate WNT in epithelial cells, it is dispensable for epithelial but crucial for mesenchymal WNT activity at the caudal embryonic MD in vivo. Moreover, conditional media derived from MAP3K1-compentent, but not -deficient, epithelial cells activate TCF-luciferase reporter in fibroblasts, suggesting MAP3K1 induces secreted activators from epithelial cells to activate WNT in fibroblasts. Correspondingly, the expression of Wnt7b is high in wild type, but low in Map3k1 knockout caudal MD epithelium and MAP3K1-deficient keratinocytes. Our data reveal a temporal-spatial paracrine MAP3K1-WNT crosstalk in the regulation of caudal MD elongation and FRT development. Overall design: Three independent samples of human epithelial HaCaT cells genetically-modified to have increased (SAM) MAP3K1 expression were compared to three independent samples of human epithelial HaCaT cells genetically-modified to have decreased (shRNA) MAP3K1 expression.