SEK1/MKK4-Mediated SAPK/JNK Signaling Participates in Embryonic Hepatoblast Proliferation via a Pathway Different from NF-κB-Induced Anti-Apoptosis

Mice lacking the stress-signaling kinase SEK1 die from embryonic day 10.5 (E10.5) to E12.5. Although a defect in liver formation is accompanied with the embryonic lethality of sek1 −/− mice, the mechanism of the liver defect has remained unknown. In the present study, we first produced a monoclonal antibody specifically recognizing murine hepatoblasts for the analysis of liver development and further investigated genetic interaction of sek1 with tumor necrosis factor-α receptor 1 gene ( tnfr1) and protooncogene c-jun, which are also responsible for liver formation and cell apoptosis. The defective liver formation in sek1 −/− embryos was not protected by additional tnfr1 mutation, which rescues the embryonic lethality of mice lacking NF-κB signaling components. There was a progressive increase in the hepatoblast cell numbers of wild-type embryos from E10.5 to E12.5. Instead, impaired hepatoblast proliferation was observed in sek1 −/− livers from E10.5, though fetal liver-specific gene expression was normal. The impaired phenotype in sek1 −/− livers was more severe than in c-jun −/− embryos, and sek1 −/− c-jun −/− embryos died more rapidly before E8.5. The hepatoblast proliferation required no hematopoiesis, since liver development was not impaired in AML1 −/− mice that lack hematopoietic functions. Stimulation of stress-activated protein kinase/c-Jun N-terminal kinase by hepatocyte growth factor was attenuated in sek1 −/− livers. Thus, SEK1 appears to play a crucial role in hepatoblast proliferation and survival in a manner apparently different from NF-κB or c-Jun.