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© The Rockefeller University Press, 0021-9525/1998//935 $5.00
The Journal of Cell Biology, Volume 140, Number 4, , 1998 935-946

Hepatocyte Nuclear Factor 4 Provokes Expression of Epithelial Marker Genes, Acting As a Morphogen in Dedifferentiated Hepatoma Cells

Unité de Génétique de la Différenciation, URA 1149, Centre National de la Recherche Scientifique, Département de Biologie Moléculaire, Institut Pasteur, 75724 Paris, France

Abstract. We have recently shown that stable expression of an epitope-tagged cDNA of the hepatocyte- enriched transcription factor, hepatocyte nuclear factor (HNF)4, in dedifferentiated rat hepatoma H5 cells is sufficient to provoke reexpression of a set of hepatocyte marker genes. Here, we demonstrate that the effects of HNF4 expression extend to the reestablishment of differentiated epithelial cell morphology and simple epithelial polarity. The acquisition of epithelial morphology occurs in two steps. First, expression of HNF4 results in reexpression of cytokeratin proteins and partial reestablishment of E-cadherin production. Only the transfectants are competent to respond to the synthetic glucocorticoid dexamethasone, which induces the second step of morphogenesis, including formation of the junctional complex and expression of a polarized cell phenotype. Cell fusion experiments revealed that the transfectant cells, which show only partial restoration of E-cadherin expression, produce an extinguisher that is capable of acting in trans to downregulate the E-cadherin gene of well-differentiated hepatoma cells. Bypass of this repression by stable expression of E-cadherin in H5 cells is sufficient to establish some epithelial cell characteristics, implying that the morphogenic potential of HNF4 in hepatic cells acts via activation of the E-cadherin gene. Thus, HNF4 seems to integrate the genetic programs of liver-specific gene expression and epithelial morphogenesis.

G. Späth was supported by a fellowship from the Human Capital Mobility Programme of the European Economic Community (EEC). This work was supported in part by contracts from the Biotechnology Programme of the EEC under contract No. BIOT CT 93-0103, and from the Association pour la Recherche sur le Cancer.

Address all correspondence to Mary C. Weiss, Institut Pasteur, Unité de Génétique de la Différenciation, 25 rue du Dr. Roux, 75724 Paris cedex 15, France. Tel. 33-1-45-68-85-00. Fax: 33-1-40-61-32-31. E-mail: mweiss{at}pasteur.fr

1. Abbreviations used in this paper: 1-AT, 1-antitrypsin; CMV, cytomegalovirus; Dex, dexamethasone; HNF, hepatocyte nuclear factor; ZO, zonula occludens.

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