Inducible inactivation of Notch1 causes nodular regenerative hyperplasia in mice.
The discovery that the human Jagged1 gene (JAG1) is the Alagille syndrome disease gene indicated that Notch signaling has an important role in bile duct homeostasis. The functional study of this signaling pathway has been difficult because mice with targeted mutations in Jagged1, Notch1, or Notch2 have an embryonic lethal phenotype. We have previously generated mice with inducible Notch1 disruption using an interferon-inducible Cre-recombinase transgene in combination with the loxP flanked Notch1 gene. We used this conditional Notch1 knockout mouse model to investigate the role of Notch1 signaling in liver cell proliferation and differentiation. Deletion of Notch1 did not result in bile duct paucity, but, surprisingly, resulted in a continuous proliferation of hepatocytes. In conclusion, within weeks after Notch1 inactivation, the mice developed nodular regenerative hyperplasia without vascular changes in the liver.
Croquelois
Adrien
A
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland.
Blindenbacher
Alex
A
Terracciano
Luigi
L
Wang
Xueya
X
Langer
Igor
I
Radtke
Freddy
F
Heim
Markus H
MH
D000818:Animals; D002135:Calcium-Binding Proteins; D049109:Cell Proliferation; D020518:Focal Nodular Hyperplasia / Q000209:etiology*; D006498:Hepatectomy; D022781:Hepatocytes / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008115:Liver Regeneration; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000235:genetics / Q000502:physiology; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D011506:Proteins; D000072099:Serrate-Jagged Proteins