Liver Biology/Pathobiology

Bile duct proliferation inJag1/fringe heterozygous mice identifies candidate modifiers of the alagille syndrome hepatic phenotype

Ryan, Matthew J.1,4; Bales, Christina1; Nelson, Anthony1; Gonzalez, Dorian M.2; Underkoffler, Lara1; Segalov, Michelle2; Wilson-Rawls, Jeanne5,6; Cole, Susan E.7; Moran, Jennifer L.8; Russo, Pierre3,4; Spinner, Nancy B.2,3,4; Kusumi, Kenro2,4,5,6; Loomes, Kathleen M.1,4*

Author Information

1Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA

2Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia, Philadelphia, PA

3Department of Pathology and Clinical Laboratories, Children's Hospital of Philadelphia, Philadelphia, PA

4Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA

5School of Life Sciences, Arizona State University, Tempe, AZ

6Department of Basic Medical Sciences, University of Arizona College of Medicine–Phoenix in Partnership with Arizona State University, Phoenix, AZ

7Department of Molecular Genetics, Ohio State University, Columbus, OH

8Genetic Analysis Platform, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA

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

Email:[email protected]

Received 22 February 2008; Accepted 15 July 2008

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

Supported by National Institutes of Health; Grant Numbers: DK53104 DK071841 AR050687; Grant sponsor: Hitchings-Elion Fellowship of the Burroughs Wellcome Fund; Grant sponsor: Children's Digestive Health and Nutrition Foundation Young Investigator's Development Award; Grant sponsor: Morphology Core of the Center for Molecular Studies of the Liver and Digestive Disease; Grant Number: P30 DK50306; Grant sponsor: Fred and Suzanne Biesecker Pediatric Liver Center.

Potential conflict of interest: Nothing to report.

fax: 267-426-7814

Hepatology 48(6):p 1989-1997, December 2008. | DOI: 10.1002/hep.22538

Abstract

Alagille syndrome (AGS) is a heterogeneous developmental disorder associated with bile duct paucity and various organ anomalies. The syndrome is caused by mutations inJAG1, which encodes a ligand in the Notch signaling pathway, in the majority of cases and mutations in theNOTCH2receptor gene in less than 1% of patients. Although a wide array ofJAG1mutations have been identified in the AGS population, these mutational variants have not accounted for the wide phenotypic variability observed in patients with this syndrome. The Fringe genes encode glycosyltransferases, which modify Notch and alter ligand-receptor affinity. In this study, we analyzed double heterozygous mouse models to examine the Fringe genes as potential modifiers of the Notch-mediated hepatic phenotype observed in AGS. We generated mice that were haploinsufficient for bothJag1and one of three paralogous Fringe genes: Lunatic (Lfng), Radical (Rfng), and Manic (Mfng). AdultJag1+/−Lfng+/− andJag1+/−Rfng+/− mouse livers exhibited widespread bile duct proliferation beginning at 5 weeks of age and persisting up to 1 year. TheJag1+/−Mfng+/− livers showed a subtle, yet significant increase in bile duct numbers and bile duct to portal tract ratios. These abnormalities were not observed in the newborn period. Despite the portal tract expansion by bile ducts, fibrosis was not increased and epithelial to mesenchymal transition was not shown in the affected portal tracts.Conclusion:Mice heterozygous for mutations inJag1and the Fringe genes display striking bile duct proliferation, which is not apparent at birth. These findings suggest that the Fringe genes may regulate postnatal bile duct growth and remodeling, and serve as candidate modifiers of the hepatic phenotype in AGS. (Hepatology 2008;48:1989–1997.)

Abbreviations: AGS, Alagille syndrome; Dll1, Delta-like 1; IHC, immunohistochemistry; Lfng, Lunatic Fringe; Rfng, Radical Fringe; Mfng, Manic Fringe.

Copyright © 2008 American Association for the Study of Liver Diseases.

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