Coffinier Catherine, Gresh Lionel, Fiette Laurence, Tronche François, Schütz Günther, Babinet Charles, Pontoglio Marco, Yaniv Moshe, Barra Jacqueline
Unité des Virus Oncogènes-CNRS URA 1644, Institut Pasteur, 25, rue du Docteur Roux, 75724 Paris Cedex 15, France.
Development. 2002 Apr;129(8):1829-38. doi: 10.1242/dev.129.8.1829.
The inactivation of the Hnf1beta 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 HNF1beta 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 HNF1beta target genes involved in bile acids sensing and in fatty acid oxidation.
Hnf1beta基因的失活在内脏内胚层上皮分化中发挥了重要作用，并导致早期胚胎死亡。在本研究中，我们利用Cre/loxP系统在肝细胞和胆管细胞中特异性地使该基因失活。突变动物表现出由胆囊和肝内胆管（IHBD）异常引起的严重黄疸。IHBD小分支的稀少与肝脏器官发生过程中导管结构组织的失败有关，提示Hnf1b在胆管形态发生中具有重要功能。突变小鼠还缺乏小叶间动脉。由于HNF1beta在这些细胞中不表达，这进一步强调了动脉和胆管形成之间的联系。肝细胞代谢也受到影响，我们鉴定出了参与胆汁酸感知和脂肪酸氧化的肝细胞特异性HNF1beta靶基因。
