Inducible inactivation of Notch1 causes nodular regenerative hyperplasia in mice

Authors

  • Adrien Croquelois,

    1. Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland
    2. Division of Hypertension, University of Lausanne Medical School, Lausanne, Switzerland
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    • A.C., A.B., and L.T. contributed equally to this work.

  • Alex Blindenbacher,

    1. Department of Research, University Hospital Basel, Basel, Switzerland
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    • A.C., A.B., and L.T. contributed equally to this work.

  • Luigi Terracciano,

    1. Institute of Pathology, University Hospital Basel, Basel, Switzerland
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    • A.C., A.B., and L.T. contributed equally to this work.

  • Xueya Wang,

    1. Department of Research, University Hospital Basel, Basel, Switzerland
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  • Igor Langer,

    1. Department of Surgery, University Hospital Basel, Basel, Switzerland
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  • Freddy Radtke,

    1. Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland
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  • Markus H. Heim

    Corresponding author
    1. Department of Research, University Hospital Basel, Basel, Switzerland
    2. Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
    • Department of Research, University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
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    • fax: (41) 61 265 53 52.


  • Conflict of interest: Nothing to report.

  • See Editorial on page 439

Abstract

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. (HEPATOLOGY 2005;41:487–496.)

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