Assessing developmental roles of MKK4 and MKK7 in vitro

In vivo gene knockout studies in mice have revealed essential roles of the mitogen-activated protein kinases (MAPKs) in embryogenesis, but due to early lethality of the knockout embryos, the underlying mechanisms and specific developmental programs regulated by the MAPK pathways have remained largely unknown. In vitro differentiation of mouse embryonic stem cells (ESCs) have opened new possibilities for understanding lineage segregation and gene function in the developmental stages that are not normally accessible in vivo. Building on this technology, in combination with gene knockout cells, we investigated the roles of MKK4 and MKK7, two upstream kinases of the MAPKs, in early lineage specification. Our results show that MKK4 and MKK7 differentially regulate the JNK and p38 MAPKs and make distinct contributions to differentiation programs. In vitro ESC differentiation is a valuable system to investigate the molecular and signaling mechanisms of early embryogenesis.