Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha.
HNF-4alpha 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-4alpha 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-4alpha toward liver development and hepatocyte differentiation. However, we have shown that complementation of HNF-4alpha(-/-) embryos with a tetraploid embryo-derived wild-type visceral endoderm rescues this early developmental arrest and allows HNF-4alpha(-/-) embryos to proceed normally through midgestation stages of development. Examination of these rescued embryos revealed that HNF-4alpha was dispensable for specification and early development of the liver. However, HNF-4alpha(-/-) 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-4alpha is essential for expression of the transcription factors HNF-1alpha and PXR within the fetal liver. We therefore conclude that HNF-4alpha is both essential for hepatocyte differentiation during mammalian liver development and also crucial for metabolic regulation and liver function.
Li
J
J
Department of Cell Biology, Medical College of Wisconsin, Milwaukee, Wisconsin 53211 USA.
Ning
G
G
Duncan
S A
SA
D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001053:Apolipoproteins / Q000096:biosynthesis / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002449:Cell Aggregation; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D018920:Coculture Techniques; D004268:DNA-Binding Proteins; D004707:Endoderm / Q000473:pathology; D005775:Gastrula / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D051557:Hepatocyte Nuclear Factor 4; D008099:Liver / Q000166:cytology* / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells; D014157:Transcription Factors / Q000502:physiology*
D000209:Acute-Phase Proteins; D001053:Apolipoproteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D010750:Phosphoproteins; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors