Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice

Abstract

The Notch pathway is an evolutionary conserved, intercellular signaling pathway that plays an important role in cell fate specification and the embryonic development of many organs, including the liver. In humans, mutations in the Notch receptor ligand Jagged1 gene result in defective intrahepatic bile duct (IHBD) development in Alagille syndrome. Developmental abnormalities of IHBD in mice doubly heterozygous form Jagged1 and Notch2 mutations propose that interactions of jagged1 and its receptor Notch2 are crucial for normal IHBD development. Because different cell types in the liver are involved in IHBD development and morphogenesis, the cell-specific role of Notch signaling is not entirely understood. We investigated the effect of combined or single targeted disruption of Notch1 and Notch2 specifically in hepatoblasts and hepatoblast-derived lineage cells on liver development using AlbCre transgenic mice. Hepatocyte differentiation and homeostasis were not impaired in mice after combined deletion of Notch1 and Notch2 (NIN2FF AlbCre). However, we detected irregular ductal plate structures in NIN2F/F AlbCre newborns, and further postnatal development of IHBD was severely impaired characterized by disorganized ductular structures accompanied by portal inflammation, portal fibrosis, and foci of hepatocyte feathery degeneration in adulthood. Further characterization of mutant mice with single deletion of Notch1 (N1F/F AlbCre) or Notch2 (N2F/F A1bCre) showed that Notch2 but not Notchl is indispensable for normal perinatal and postnatal IHBD development. Further reduction of Notch2 gene dosage in Notch2 conditional/mutant (N2F/LacZ AlbCre) animals further enhanced IHBD abnormalities and concomitant liver pathology. Conclusion: Notch2 is required for proper IHBD development and morphogenesis. Copyright © 2008 by the American Association for the Study of Liver Diseases.