SEK1/MKK4-mediated SAPK/JNK signaling participates in embryonic hepatoblast proliferation via a pathway different from NF-κB-induced anti-apoptosis

Tomomi Watanabe, Kentaro Nakagawa, Shinya Ohata, Daiju Kitagawa, Gen Nishitai, Jungwon Seo, Shuhei Tanemura, Nao Shimizu, Hiroyuki Kishimoto, Teiji Wada, Junken Aoki, Hiroyuki Arai, Takeshi Iwatsubo, Miyuki Mochita, Toshio Watanabe, Masanobu Satake, Yoshiaki Ito, Toshifumi Matsuyama, Tak W. Mak, Josef M. PenningerHiroshi Nishina, Toshiaki Katada

Research output: Contribution to journalArticlepeer-review

94 Citations (Scopus)

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 sek1-1- 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 sek1-1- 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 sek1-1- rivers from E10.5, though fetal liver-specific gene expression was normal. The impaired phenotype in sek1-1- livers was more severe than in c-jun-1- embryos, and sek1-1- c-jun-1- embryos died more rapidly before E8.5. The hepatoblast proliferation required no hematopoiesis, since liver development was not impaired in AML1-1- mice that lack hematopoietic functions. Stimulation of stress-activated protein kinase/c-Jun N-terminal kinase by hepatocyte growth factor was attenuated in sek1-1- 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.

Original languageEnglish
Pages (from-to)332-347
Number of pages16
JournalDevelopmental Biology
Volume250
Issue number2
DOIs
Publication statusPublished - 2002

Keywords

  • HGF
  • Hematopoiesis
  • Hepatogenesis
  • NF-κB
  • SEK1
  • c-Jun

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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