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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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References

  1. Blouin, A., Bolender, R.P. & Weibel, E.R. Distribution of organelles and membranes between hepatocytes and nonhepatocytes in the rat liver parenchyma. A stereological study. J. Cell. Biol. 72, 441–455 (1977).

    Article  CAS  Google Scholar 

  2. Kmiec, Z. Cooperation of liver cells in health and disease. Adv. Anat. Embryol. Cell. Biol. 161, 1–151 (2001).

    Article  Google Scholar 

  3. Sherlock, S. & Dooley, J. Hepatic cirrhosis. in Diseases of the Liver and Biliary System 371–382 (Blackwell Science, Oxford, 1997).

    Google Scholar 

  4. Li, J., Ning, G. & Duncan, S.A. Mammalian hepatocyte differentiation requires the transcription factor HNF-4α. Genes Dev. 14, 464–474 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen, W.S. et al. Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Genes Dev. 8, 2466–2477 (1994).

    Article  CAS  Google Scholar 

  6. Duncan, S.A., Nagy, A. & Chan, W. Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: tetraploid rescue of HNF-4−/− embryos. Development 124, 279–287 (1997).

    CAS  Google Scholar 

  7. Parviz, F., Li, J., Kaestner, K.H. & Duncan, S.A. Generation of a conditionally null allele of Hnf4α. Genesis 32, 130–133 (2002).

    Article  CAS  Google Scholar 

  8. Hayhurst, G.P., Lee, Y.H., Lambert, G., Ward, J.M. & Gonzalez, F.J. Hepatocyte nuclear factor 4α (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol. Cell. Biol. 21, 1393–1403 (2001).

    Article  CAS  Google Scholar 

  9. Hall, R.K., Sladek, F.M. & Granner, D.K. The orphan receptors COUP-TF and HNF-4 serve as accessory factors required for induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. Proc. Natl. Acad. Sci. USA 92, 412–416 (1995).

    Article  CAS  Google Scholar 

  10. Boustead, J.N. et al. Hepatocyte nuclear factor-4α (HNF-4α) mediates the stimulatory effect of peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) on glucose-6-phosphatase catalytic subunit gene transcription in H4IIE cells. Biochem. J. 369, 17–22 (2003).

    Article  CAS  Google Scholar 

  11. Vassy, J., Kraemer, M., Chalumeau, M.T. & Foucrier, J. Development of the fetal rat liver: ultrastructural and stereological study of hepatocytes. Cell. Differ. 24, 9–24 (1988).

    Article  CAS  Google Scholar 

  12. Medlock, E.S. & Haar, J.L. The liver hemopoietic environment: I. Developing hepatocytes and their role in fetal hemopoiesis. Anat. Rec. 207, 31–41 (1983).

    Article  CAS  Google Scholar 

  13. Feracci, H., Connolly, T.P., Margolis, R.N. & Hubbard, A.L. The establishment of hepatocyte cell surface polarity during fetal liver development. Dev. Biol. 123, 73–84 (1987).

    Article  CAS  Google Scholar 

  14. Wood, R.L. An electron microscope study of the developing bile canaliculi in the rat. Anat. Rec. 151, 507–503 (1965).

    Article  CAS  Google Scholar 

  15. De Wolf-Peeters, C., De Vos, R., Desmet, V., Bianchi, L. & Rohr, H.P. Electron microscopy and morphometry of canalicular differentiation in fetal and neonatal rat liver. Exp. Mol. Pathol. 21, 339–350 (1974).

    Article  CAS  Google Scholar 

  16. Daniels, E. et al. Biliary glycoprotein 1 expression during embryogenesis: correlation with events of epithelial differentiation, mesenchymal-epithelial interactions, absorption, and myogenesis. Dev. Dyn. 206, 272–290 (1996).

    Article  CAS  Google Scholar 

  17. Cascio, S. & Zaret, K.S. Hepatocyte differentiation initiates during endodermal-mesenchymal interactions prior to liver formation. Development 113, 217–225 (1991).

    CAS  PubMed  Google Scholar 

  18. Spath, G.F. & Weiss, M.C. Hepatocyte nuclear factor 4 expression overcomes repression of the hepatic phenotype in dedifferentiated hepatoma cells. Mol. Cell. Biol. 17, 1913–1922 (1997).

    Article  CAS  Google Scholar 

  19. Spath, G.F. & Weiss, M.C. Hepatocyte nuclear factor 4 provokes expression of epithelial marker genes, acting as a morphogen in dedifferentiated hepatoma cells. J. Cell. Biol. 140, 935–946 (1998).

    Article  CAS  Google Scholar 

  20. Sladek, F.M., Zhong, W., Lai, E. & Darnell, J.E., Jr. Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes. Dev. 4, 2353–2365 (1990).

    Article  CAS  Google Scholar 

  21. Pear, W.S., Nolan, G.P., Scott, M.L. & Baltimore, D. Production of high-titer helper-free retroviruses by transient transfection. Proc. Natl. Acad. Sci. USA 90, 8392–8396 (1993).

    Article  CAS  Google Scholar 

  22. Morgenstern, J.P. & Land, H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 18, 3587–3596 (1990).

    Article  CAS  Google Scholar 

  23. Enzan, H. et al. Development of hepatic sinusoidal structure with special reference to the Ito cells. Microsc. Res. Tech. 39, 336–349 (1997).

    Article  CAS  Google Scholar 

  24. Duncan, S.A. et al. Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst. Proc. Natl. Acad. Sci. USA 91, 7598–7602 (1994).

    Article  CAS  Google Scholar 

  25. Taraviras, S., Monaghan, A.P., Schutz, G. & Kelsey, G. Characterization of the mouse HNF-4 gene and its expression during mouse embryogenesis. Mech. Dev. 48, 67–79 (1994).

    Article  CAS  Google Scholar 

  26. Sund, N.J. et al. Hepatocyte nuclear factor 3β (Foxa2) is dispensable for maintaining the differentiated state of the adult hepatocyte. Mol. Cell. Biol. 20, 5175–5183 (2000).

    Article  CAS  Google Scholar 

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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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