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

Abstract

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 ofsek1 with tumor necrosis factor-alpha 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 additionaltnfr1 mutation, which rescues the embryonic lethality of mice lacking NF-kappaB 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-kappaB or c-Jun.

Vibration induced hearing loss in guinea pig cochlea: expression of TNF-α and VEGF

“…The combination of TNF-a with TNF receptor 2 is capable of activating Jun N-terminal kinases (JNK) and nuclear factor (NF)-jB (Goeddel, 1999). The activation of JNK and NF-jB has the function of antiapoptotic agent (Goeddel, 1999;Watanabe et al, 2002;Biswas et al, 2003). On contrary, the activation of TNF receptor 1 induces apoptosis (Ashkenazi and Dixit, 1998;Goeddel, 1999).…”

Fibroblast growth factor 2 facilitates the differentiation of transplanted bone marrow cells into hepatocytes

“…Mice were killed at 48 h after BMT and every week thereafter for up to 4 weeks. Immunohistochemical analysis with anti-GFP (Santa Cruz Biotechnology), anti-Liv2 (hepatoblast marker; Watanabe et al 2002), anti-albumin (Bethyl Laboratories, Tex., USA), and anti-tumor necrosis factor-α (TNF-α; TECHNE, Min., USA) antibodies was performed on these samples (n=6 in each group). The proportion of stained area was calculated by using MetaMorph software at a total of 30 random fields per group.…”

Mutations affecting liver development and function in Medaka, Oryzias latipes, screened by multiple criteria

“…For instance, we have shown using SEK1 or MKK7-deficient mice that two stresssignaling kinases, SEK1 (also called MKK4) and MKK7, play crucial roles in hepatoblast proliferation and survival (Nishina et al, 1999;Wada et al, 2004;Watanabe et al, 2002). Although a reverse genetic approach is powerful in characterizing functions of known genes, knowledge of genes, particularly in hepatic bud formation from endoderm, morphogenesis and laterality of the liver, and hemoglobinbilirubin or lipid metabolism, is still limited.…”