Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4.
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.
Nishina
H
H
The Amgen Institute, Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology, University of Toronto, Suite 706, Toronto, Ontario M5G 2C1, Canada.
Vaz
C
C
Billia
P
P
Nghiem
M
M
Sasaki
T
T
De la Pompa
J L
JL
Furlonger
K
K
Paige
C
C
Hui
C
C
Fischer
K D
KD
Kishimoto
H
H
Iwatsubo
T
T
Katada
T
T
Woodgett
J R
JR
Penninger
J M
JM
D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D018390:Gene Targeting; D006410:Hematopoiesis / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000196:embryology*; D048670:MAP Kinase Kinase 4; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases; D016296:Mutagenesis; D018919:Neovascularization, Physiologic / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*
D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases