Mammalian hepatocyte differentiation requires the transcription factor HNF-4α

  1. Jixuan Li,
  2. Gang Ning, and
  3. Stephen A. Duncan1
  1. Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53211 USA

Abstract

HNF-4α is a transcription factor of the nuclear hormone receptor family that is expressed in the hepatic diverticulum at the onset of liver development. Mouse embryos lacking HNF-4α fail to complete gastrulation due to dysfunction of the visceral endoderm. This early embryonic lethality has so far prevented any analyses of the contribution of HNF-4α toward liver development and hepatocyte differentiation. However, we have shown that complementation ofHNF-4 α −/−embryos with a tetraploid embryo-derived wild-type visceral endoderm rescues this early developmental arrest and allowsHNF-4 α −/−embryos to proceed normally through midgestation stages of development. Examination of these rescued embryos revealed that HNF-4α was dispensable for specification and early development of the liver. However,HNF-4α −/− 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 apolipoproteins, metabolic proteins, and serum factors. In addition, we have demonstrated that HNF-4α is essential for expression of the transcription factors HNF-1α and PXR within the fetal liver. We therefore conclude that HNF-4α is both essential for hepatocyte differentiation during mammalian liver development and also crucial for metabolic regulation and liver function.

Keywords

Footnotes

| Table of Contents

Life Science Alliance