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Hepatocyte nuclear factor 4α controls the development of a hepatic epithelium and liver morphogenesis

Nature Genetics volume 34, pages 292–296 (2003)Cite this article

Abstract

Although 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 4α (Hnf4α) is essential for morphological and functional differentiation of hepatocytes4, accumulation of hepatic glycogen stores and generation of a hepatic epithelium. We show that Hnf4α 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 Hnf4α in hepatocytes are essential for normal liver architecture, including the organization of the sinusoidal endothelium.

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Figure 1: Loss of Hnf4α in fetal livers disrupts hepatic architecture.
Figure 2: Accumulation of hepatic glycogen is disrupted by loss of Hnf4α.
Figure 3: Formation of a hepatic epithelium is dependent on Hnf4α.
Figure 4: Hnf4α dominantly confers an epithelial phenotype on fibroblast cells.
Figure 5: Hnf4α is necessary to maintain hepatic sinusoidal architecture.

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Acknowledgements

We thank J. Morrison for early guidance, N. Lazarevitch for advice on PCR primers, P. Traktman for critical input, N. Beauchemin for antibodies to CEACAM1 and J. Burke and D. Lourim for advice on antibodies to E-cadherin and ZO1. Funding for this project was provided by American Heart Association fellowships to F.P. and W.D.G., a Human Frontiers Science Program grant to K.S.Z. and S.A.D. and grants from the US National Institutes of Health to K.S.Z. and S.A.D.

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Authors and Affiliations

  1. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, 53226, Wisconsin, USA

    Fereshteh Parviz, Wendy D Garrison, Gang Ning & Stephen A Duncan

  2. Cell and Developmental Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

    Christine Matullo, Jennifer M Rossi & Kenneth S Zaret

  3. The Blood Research Institute, Blood Center of Southeastern Wisconsin, 8727 Watertown Plank Road, Milwaukee, 53226, Wisconsin, USA

    Laura Savatski & John W Adamson

  4. Department of Genetics, University of Pennsylvania Medical School, Philadelphia, Pennsylvania, USA

    Klaus H Kaestner

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  1. Fereshteh Parviz
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Correspondence to Stephen A Duncan.

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Parviz, F., Matullo, C., Garrison, W. et al. Hepatocyte nuclear factor 4α controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet 34, 292–296 (2003). https://doi.org/10.1038/ng1175

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