Biochemistry, Rappaport Medical School, Technion-Israel Institute of Technology, Haifa
Dorsal-ventral patterning is specified by the early formation of signaling centers secreting morphogens and their antagonists that form signaling gradients. Yet, how morphogen gradient is translated intracellularly into fate decisions remains largely unknown. Here, we report that p38 MAPK and the CREB transcription factor function along the dorsal-ventral axis in mesoderm patterning. We find that the phosphorylated form of CREB (S133) is distributed in a gradient along the dorsal-ventral mesoderm axis at the gastrula stage and that the p38 MAPK pathway mediates the phosphorylation of CREB. Knockdown of CREB prevents chordin expression and mesoderm dorsalization by the Spemann organizer, whereas ectopic expression of activated CREB-VP16 chimera induces chordin expression and dorsalizes mesoderm. Likewise, expression of high levels of p38 activator, MKK6E in embryos converts ventral mesoderm into a dorsal organizing center while knockdown of p38α converts dorsal into ventral mesoderm. p38 MAPK and CREB function downstream of maternal Wnt/β-catenin and the organizer-specific genes siamois and goosecoid. These data indicate that dorsal-ventral mesoderm patterning is regulated by differential p38/CREB activities along the axis. Recently, we identified an earlier involvement of the Mef2D transcription factor in the formation of the dorsal organizer. We will present data supporting the direct involvement of Mef2D in the expression of mesoderm and organizer-specific genes at the blastula stage. Overall, these findings reveal a complex network of transcriptional/signaling program regulating mesoderm patterning.