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Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1ß

Catherine Coffinier^1,*,, Lionel Gresh^1,, Laurence Fiette², François Tronche^3,, Günther Schütz³, Charles Babinet⁴, Marco Pontoglio¹, Moshe Yaniv^1, and Jacqueline Barra⁴

¹ Unité des Virus Oncogènes-CNRS URA 1644, Institut Pasteur, 25, rue du Docteur Roux, 75724 Paris Cedex 15, France
² Unité d’Expertise en Histotechnologie et Pathologie, Institut Pasteur, 25, rue du Docteur Roux, 75724 Paris Cedex 15, France
³ Division Molecular Biology of the Cell I, DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
⁴ Unité de Biologie du Développement-CNRS URA 1960, Institut Pasteur, 25, rue du Docteur Roux, 75724 Paris Cedex 15, France
^* Present address: Howard Hughes Medical Institute-UCLA, Los Angeles, CA 90095-1662, USA
Present address: Institut de Biologie, CNRS FRE 2401, Collège de France, 11, place Marcelin Berthelot, 75231 Paris Cedex 5, France
Both authors contributed equally to this work

Author for correspondence (e-mail: yaniv{at}pasteur.fr)

Accepted 21 January 2002

The inactivation of the Hnf1ß gene identified an essential role in epithelial differentiation of the visceral endoderm and resulted in early embryonic death. In the present study, we have specifically inactivated this gene in hepatocytes and bile duct cells using the Cre/loxP system. Mutant animals exhibited severe jaundice caused by abnormalities of the gallbladder and intrahepatic bile ducts (IHBD). The paucity of small IHBD was linked to a failure in the organization of duct structures during liver organogenesis, suggesting an essential function of Hnf1b in bile duct morphogenesis. Mutant mice also lacked interlobular arteries. As HNF1ß is not expressed in these cells, it further emphasizes the link between arterial and biliary formation. Hepatocyte metabolism was also affected and we identified hepatocyte-specific HNF1ß target genes involved in bile acids sensing and in fatty acid oxidation.

Key words: Cre/loxP, Bile duct, Epithelium differentiation, Gallbladder, Lipids

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