Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4

  • Development. 1999 Feb;126(3):505-16. doi: 10.1242/dev.126.3.505.
H Nishina  1 ,  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
Affiliations
  • 1. The Amgen Institute, Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology, University of Toronto, Suite 706, Toronto, Ontario M5G 2C1, Canada.
PMID: 9876179 DOI: 10.1242/dev.126.3.505
Abstract

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.