Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4

The stress signaling kinase SEK1/MKK4 is a direct activator of stress-activ ated protein kinases (SAPKs; also called Jun-N-terminal kinases, JNKs) in r esponse to a variety of cellular stresses, such as changes in osmolarity, m etabolic poisons, DNA damage, heat shock or inflammatory cytokines. We have disrupted the sek1 gene in mice using homologous recombination, Sek1(-/-) embryos display severe anemia and die between embryonic day 10.5 (E10.5) an d E12.5. Haematopoiesis from yolk sac precursors and vasculogenesis are nor mal in sek1(-/-) embryos, However, hepatogenesis and liver formation were s everely impaired in the mutant embryos and E11.5 and E12.5 sek1(-/-) embryo s had greatly reduced numbers of parenchymal hepatocytes. Whereas formation of the primordial liver from the visceral endoderm appeared normal, sek1(- /-) liver cells underwent massive apoptosis, These results provide the firs t genetic link between stress-responsive kinases and organogenesis in mamma ls and indicate that SEK1 provides a crucial and specific survival signal f or hepatocytes.