Nrf1 is critical for redox balance and survival of liver cells during development.
The Nrf1 transcription factor belongs to the CNC subfamily of basic leucine zipper proteins. Knockout of Nrf1 is lethal in mouse embryos, but nothing is known about the cell types that absolutely require its function during development. We show by chimera analysis that Nrf1 is essential for the hepatocyte lineage. Mouse embryonic stem cells lacking Nrf1 developed normally and contributed to most tissues in adult chimeras where Nrf1 is normally expressed. Nrf1-deficient cells contributed to fetal, but not adult, liver cells. Loss of Nrf1 function resulted in liver cell apoptosis in late-gestation chimeric fetuses. Fetal livers from mutant embryos exhibited increased oxidative stress and impaired expression of antioxidant genes, and primary cultures of nrf1(-/-) fetal hepatocytes were sensitive to tert-butyl hydroperoxide-induced cell death, suggesting that impaired antioxidant defense may be responsible for the apoptosis observed in the livers of chimeric mice. In addition, cells deficient in Nrf1 were sensitized to the cytotoxic effects of tumor necrosis factor (TNF). Our results provide in vivo evidence demonstrating an essential role of Nrf1 in the survival of hepatocytes during development. Our results also suggest that Nrf1 may promote cell survival by maintaining redox balance and protecting embryonic hepatocytes from TNF-mediated apoptosis during development.
Chen
Linyun
L
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California 94143, USA.
Kwong
Mandy
M
Lu
Ronghua
R
Ginzinger
David
D
Lee
Candy
C
Leung
Laura
L
Chan
Jefferson Y
JY
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002455:Cell Division; D019070:Cell Lineage; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007763:Lac Operon; D008099:Liver / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology; D014018:Tissue Distribution; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D004268:DNA-Binding Proteins; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione