CCAAT/enhancer-binding protein α is required for hepatic outgrowth via the p53 pathway in zebrafish

CCAAT/enhancer-binding protein alpha (C/ebp alpha) is a transcription factor that plays important roles in the regulation of hepatogenesis, adipogenesis and hematopoiesis. Disruption of the C/EBP alpha gene in mice leads to disturbed liver architecture and neonatal death due to hypoglycemia. However, the precise stages of liver development affected by C/ebp alpha loss are poorly studied. Using the zebrafish embryo as a model organism, we show that inactivation of the cebpa gene by TALENs results in a small liver phenotype. Further studies reveal that C/ebp alpha is distinctively required for hepatic outgrowth but not for hepatoblast specification. Lack of C/ebp alpha leads to enhanced hepatic cell proliferation and subsequent increased cell apoptosis. Additional loss of p53 can largely rescue the hepatic defect in cebpa mutants, suggesting that C/ebp alpha plays a role in liver growth regulation via the p53 pathway. Thus, our findings for the first time demonstrate a stage-specific role for C/ebp alpha during liver organogenesis.