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

Summary

Mice lacking the stress-signaling kinases SEK1 and MKK7 die from embryonic day 10.5 (E10.5) to E12.5 with a defect in liver formation. However, the mechanism of the liver defect has remained unknown. In this review, we first introduce a monoclonal antibody, anti-Liv2, which specifically recognizes murine hepatoblasts, for the analysis of liver development, and further, we describe the genetic interaction of sek1 with the tumor necrosis factor-α receptor 1 gene (tnfr1) and the protooncogene c-jun, which are also responsible for liver formation and cell apoptosis. The defective liver formation in sek1 ^-/- embryos was not protected by an additional tnfr1 mutation that rescues the embryonic lethality of mice lacking nuclear factor-kappa B (NF-κB) signaling components. There was a progressive increase in hepatoblast cell numbers in wild-type embryos from E10.5 to E12.5. In contrast, impaired hepatoblast proliferation was observed in sek1 ^-/- livers from E10.5, although fetal liver-specific gene expression was normal. The impaired phenotype in sek1 ^-/- livers was more severe than that in c-jun ^-/- embryos, and sek1 ^-/- c-jun ^-/- embryos died earlier before E8.5. The hepatoblast proliferation required no hematopoiesis, because liver development was not impaired in AML1 ^-/- mice, which lack hematopoietic functions. Stimulation of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) by hepatocyte growth factor was attenuated in sek1 ^-/- livers. Thus, SEK1 and MKK7-mediated SAPK/JNK signaling appears to playa crucial role in hepatoblast proliferation and survival in a manner that is apparently different from that of NF-κB or c-Jun.