Nature Genetics
34, 292 - 296 (2003)
Published online: 15 June 2003; | doi:10.1038/ng1175
Hepatocyte nuclear factor 4 controls the development of a hepatic epithelium and liver morphogenesisFereshteh Parviz1, Christine Matullo2, Wendy D Garrison1, Laura Savatski3, John W Adamson3, Gang Ning1, Klaus H Kaestner4, Jennifer M Rossi2, Kenneth S Zaret2
& Stephen A Duncan11
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. 2
Cell and Developmental Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. 3
The Blood Research Institute, Blood Center of Southeastern Wisconsin, 8727 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA. 4
Department of Genetics, University of Pennsylvania Medical School, Philadelphia, Pennsylvania, USA.
Correspondence should be addressed to Stephen A Duncan duncans@mcw.eduAlthough advances have been made in understanding cell differentiation, only rudimentary knowledge exists concerning how differentiated cells form tissues and organs. We studied liver organogenesis because the cell and tissue architecture of this organ is well defined. Approximately 60% of the adult liver consists of hepatocytes that are arranged as single-cell anastomosing plates extending from the portal region of the liver lobule toward the central vein1. The basal surface of the hepatocytes is separated from adjacent sinusoidal endothelial cells by the space of Disse, where the exchange of substances between serum and hepatocytes takes place. The hepatocyte's apical surface forms bile canaliculi that transport bile to the hepatic ducts. Proper liver architecture is crucial for hepatic function2 and is commonly disrupted in disease states, including cirrhosis and hepatitis3. Here we report that hepatocyte nuclear factor 4 (Hnf4) is essential for morphological and functional differentiation of hepatocytes4, accumulation of hepatic glycogen stores and generation of a hepatic epithelium. We show that Hnf4 is a dominant regulator of the epithelial phenotype because its ectopic expression in fibroblasts induces a mesenchymal-to-epithelial transition. Most importantly, the morphogenetic parameters controlled by Hnf4 in hepatocytes are essential for normal liver architecture, including the organization of the sinusoidal endothelium.
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