Bile duct proliferation in liver-specificJag1conditional... : Hepatology (original) (raw)

Original Articles

Bile duct proliferation in liver-specific Jag1 conditional knockout mice: Effects of gene dosage

Loomes, Kathleen M.1,2*; Russo, Pierre3,4; Ryan, Matthew1,2; Nelson, Anthony1; Underkoffler, Lara1; Glover, Curtis1; Fu, Hong5; Gridley, Thomas6; Kaestner, Klaus H.5; Oakey, Rebecca J.7

1_Division of Gastroenterology, Hepatology & Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA_

2_Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA_

3_Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA_

4_Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA_

5_Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA_

6_Jackson Laboratory, Bar Harbor, ME_

7_King's College London, Department of Medical and Molecular Genetics, London, UK_

*Address reprint requests to: Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104

Email:[email protected]

Received 27 July 2006; Accepted 11 August 2006

Published online 5 January 2007 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: NIH; Grant Numbers: P50HL62177 DK55342 NS036437 DK02796 DK071841; Grant sponsor: Fred and Suzanne Biesecker Pediatric Liver Center at the Children's Hospital of Philadelphia.

Potential conflict of interest: Nothing to report.

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Abstract

The Notch signaling pathway is involved in determination of cell fate and control of cell proliferation in multiple organ systems. Jag1 encodes a ligand in the Notch pathway and has been identified as the disease-causing gene for the developmental disorder Alagille syndrome. Evidence from the study of human disease and mouse models has implicated Jag1 as having an important role in the development of bile ducts. We have derived a conditional knockout allele ( Jag1 loxP) to study the role of Jag1 and Notch signaling in liver and bile duct development. We crossed Jag1 loxP mice with a transgenic line carrying Cre recombinase under the control of the albumin promoter and α-fetoprotein enhancer to ablate Jag1 in hepatoblasts. The liver-specific Jag1 conditional knockout mice showed normal bile duct development. To further decrease Notch pathway function, we crossed the Jag1 conditional knockout mice with mice carrying the hypomorphic Notch2 allele, and bile duct anatomy remained normal. When Jag1 conditional mice were crossed with mice carrying the Jag1 null allele, the adult progeny exhibited striking bile duct proliferation.

Conclusion:

These results indicate that Notch signaling in the liver is sensitive to Jag1 gene dosage and suggest a role for the Notch pathway in postnatal growth and morphogenesis of bile ducts.

Abbreviations: AGS, Alagille syndrome.