Mammalian hepatocyte differentiation requires the transcription factor HNF-4 alpha

HNF-4 alpha is a transcription factor of the nuclear hormone receptor famil y that is expressed in the hepatic diverticulum at the onset of liver devel opment. Mouse embryos lacking HNF-4 alpha fail to complete gastrulation due to dysfunction of the visceral endoderm. This early embryonic lethality ha s so far prevented any analyses of the contribution of HNF-4 alpha toward l iver development and hepatocyte differentiation. However, we have shown tha t complementation of HNF-4 alpha(-/-) embryos with a tetraploid embryo-deri ved wild-type visceral endoderm rescues this early developmental arrest and allows HNF-4 alpha(-/-) embryos to proceed normally through midgestation s tages of development. Examination of these rescued embryos revealed that HN F-4 alpha was dispensable for specification and early development of the li ver. However, HNF-4 alpha(-/-) fetal livers failed to express a large array of genes whose expression in differentiated hepatocytes is essential for a functional hepatic parenchyma, including genes encoding several apolipopro teins, metabolic proteins, and serum factors. In addition, we have demonstr ated that HNF-4 alpha is essential for expression of the transcription fact ors HNF-1 alpha and PXR within the fetal liver. We therefore conclude that HNF-4 alpha is both essential for hepatocyte differentiation during mammali an liver development and also crucial for metabolic regulation and liver fu nction.