Signal transduction mechanisms involved in mouse embryonic liver formation

小鼠胚胎肝脏形成中涉及的信号转导机制

基本信息

批准号：
12470493
负责人：
NISHINA Hiroshi
金额：
$ 8.9万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470493/
关键词：
fetal liver hepatic bud MAP kinase SEK1 JNK c-Jun hematopoietic stem cells NFκB MAPキナ-ゼ AML-1

项目摘要

Mice lacking 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 leading to the liver defect has remained unknown. Here we investigated liver development in sek1-/- embryos using a monoclonal antibody specifically recognizing murine hepatoblasts and genetic interaction of sek1 with proto-oncogene c-jun and tumor necrosis factor-α receptor 1 gene, tnfr1, which are also responsible for liver formation and the cell apoptosis. There was a progressive increase in the hepatoblast cell numbers of wild-type embryos from E10.5 to 12.5. The hepatoblast proliferation required no hematopoiesis, since transcription factor AML1-deficient mice had no defect in the cell growth. 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 more rapidly died before E8.5. Stimulation of stress-activatied protein kinase/c-Jun N-terminal kinase by hepatocyte growth factor was attenuated in sek1-/- livers. The defective liver formation in sek1-/- embryos was not protected by additional tnfr1 mutation that rescues the embryonic lethality of mice lacking NF-κB signaling components. Thus, SEK1 appears to play a crucial role in hepatoblast proliferation and survival in a manner apparently different from c-Jun or NF-κB.

缺乏应激信号激酶 SEK1 的小鼠从胚胎第 10.5 天 (E10.5) 到 E12.5 死亡。尽管肝脏形成缺陷伴随着 sek1-/- 小鼠的胚胎致死，但导致肝脏缺陷的机制仍然存在。在此，我们使用特异性识别小鼠成肝细胞的单克隆抗体研究了 sek1-/- 胚胎的肝脏发育以及 sek1 与原癌基因的遗传相互作用。 c-jun 和肿瘤坏死因子-α 受体 1 基因 tnfr1，也负责肝脏形成和细胞凋亡。野生型胚胎的成肝细胞数量从 E10.5 逐渐增加到 12.5。增殖不需要造血，因为转录因子 AML1 缺陷的小鼠没有细胞生长缺陷，相反，在 sek1-/- 中观察到肝细胞增殖受损。尽管胎儿肝脏特异性基因表达正常，但 sek1-/- 肝脏中受损的表型比 c-jun-/- 胚胎和 sek1-/- c-jun-/- 胚胎更严重。在 E8.5 之前，肝细胞生长因子对应激激活蛋白激酶/c-Jun N 末端激酶的刺激在 sek1-/- 肝脏中减弱。 sek1-/-胚胎中的形成不受额外的tnfr1突变的保护，而tnfr1突变可以挽救缺乏NF-κB信号成分的小鼠的胚胎致死性，因此，SEK1似乎以与c-明显不同的方式在肝母细胞增殖和存活中发挥着至关重要的作用。 Jun 或 NF-κB。