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Impaired postnatal hepatocyte proliferation and liver regeneration in mice lacking c-jun in the liver
Axel Behrens1, Maria Sibilia, Jean-Pierre David
1Research Institute of Molecular Pathology (IMP), Dr Bohr-Gasse 7, A-1030 Vienna, Austria.
Abstract:
Mice lacking the AP-1 transcription factor c-jun die at mid-gestation showing heart defects and impaired hepatogenesis. To inactivate c-jun in hepatocytes, mice carrying a floxed c-jun allele were generated. Perinatal liver-specific c-jun deletion caused reduced hepatocyte proliferation and decreased body size. After partial hepatectomy, half of the mutants died and liver regeneration was impaired. This phenotype was not present in mice lacking the N-terminal phosphorylation sites of c-Jun. The failure to regenerate was accompanied by increased cell death and lipid accumulation in hepatocytes. Moreover, cyclin-dependent kinases and several cell cycle regulators were affected, resulting in inefficient G(1)-S phase progression. These studies identify c-Jun as a critical regulator of hepatocyte proliferation and survival during liver development and regeneration.
Insights
Mice lacking the AP-1 transcription factor c-Jun show impaired liver development and regeneration. This highlights c-Jun
Area of Science:
- Molecular Biology
- Developmental Biology
- Hepatology
Background:
- The transcription factor c-Jun, a component of AP-1, is essential for embryonic development.
- Mice lacking c-Jun exhibit severe developmental defects, including heart abnormalities and impaired liver formation.
- The specific role of c-Jun in adult liver regeneration remains unclear.
Purpose of the Study:
- To investigate the function of c-Jun in hepatocyte proliferation and liver regeneration.
- To determine the impact of c-Jun inactivation in hepatocytes on liver development and post-injury repair.
Main Methods:
- Generation of mice with a floxed c-jun allele for conditional inactivation in hepatocytes.
- Analysis of liver development and regeneration following partial hepatectomy in c-Jun deficient mice.
- Assessment of cell cycle progression, cell death, and lipid accumulation in hepatocytes.
Main Results:
- Perinatal liver-specific deletion of c-Jun led to reduced hepatocyte proliferation and smaller body size.
- Mice with c-Jun deficient livers showed impaired regeneration and high mortality after partial hepatectomy.
- Failure in regeneration was associated with increased hepatocyte cell death, lipid accumulation, and dysregulation of cell cycle regulators, including inefficient G(1)-S phase transition.
Conclusions:
- c-Jun is a critical regulator of hepatocyte proliferation and survival during liver development.
- c-Jun plays an indispensable role in liver regeneration after injury.
- Inactivation of c-Jun disrupts cell cycle progression and promotes cell death, hindering liver repair.