The stress signaling kinase SEK1/MKK4 is a direct activator of stress-activated protein kinases (SAPKs; also called Jun-N-terminal kinases, JNKs) in response to a variety of cellular stresses, such as changes in osmolarity, metabolic poisons, DNA damage, heat shock or inflammatory cytokines. We have disrupted the sek1 gene in mice using homologous recombination. Sek1(−/−)embryos display severe anemia and die between embryonic day 10.5 (E10.5) and E12.5. Haematopoiesis from yolk sac precursors and vasculogenesis are normal in sek1(−/−)embryos. However, hepatogenesis and liver formation were severely impaired in the mutant embryos and E11.5 and E12.5 sek1(−/−)embryos had greatly reduced numbers of parenchymal hepatocytes. Whereas formation of the primordial liver from the visceral endoderm appeared normal, sek1(−/−) liver cells underwent massive apoptosis. These results provide the first genetic link between stress-responsive kinases and organogenesis in mammals and indicate that SEK1 provides a crucial and specific survival signal for hepatocytes.
Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4
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H. Nishina, C. Vaz, P. Billia, M. Nghiem, T. Sasaki, J.L. De la Pompa, K. Furlonger, C. Paige, C. Hui, K.D. Fischer, H. Kishimoto, T. Iwatsubo, T. Katada, J.R. Woodgett, J.M. Penninger; Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4. Development 1 February 1999; 126 (3): 505–516. doi: https://doi.org/10.1242/dev.126.3.505
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