Related Experiment Videos
Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4
1The Amgen Institute, Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology, University of Toronto, Suite 706, Toronto, Ontario M5G 2C1, Canada.
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.
Insights
The stress-responsive kinase SEK1/MKK4 is essential for mammalian organogenesis. Disruption of the SEK1 gene causes severe anemia and impaired liver development due to hepatocyte apoptosis.
Area of Science:
- Cellular biology
- Developmental biology
- Genetics
Background:
- SEK1/MKK4 is a key activator of stress-activated protein kinases (SAPKs/JNKs) in response to cellular stress.
- SAPKs/JNKs play critical roles in cellular responses to various environmental and internal stimuli.
Purpose of the Study:
- To investigate the role of SEK1/MKK4 in mammalian development using a genetic approach.
- To determine the function of SEK1 in organogenesis, particularly liver development.
Main Methods:
- Homologous recombination was used to disrupt the sek1 gene in mice, creating sek1(-/-) knockout embryos.
- Embryonic development, including hematopoiesis, vasculogenesis, and hepatogenesis, was analyzed in sek1(-/-) and wild-type embryos.
Main Results:
- Sek1(-/-) embryos exhibited severe anemia and embryonic lethality between E10.5 and E12.5.
- While hematopoiesis and vasculogenesis were unaffected, hepatogenesis and liver formation were severely impaired in mutant embryos.
- Sek1(-/-) liver cells underwent massive apoptosis, leading to a significant reduction in hepatocytes.
Conclusions:
- This study establishes the first genetic link between stress-responsive kinases and mammalian organogenesis.
- SEK1/MKK4 provides a critical survival signal for hepatocytes, highlighting its essential role in liver development.