A genetic screen in zebrafish identifies the mutantsvps18, nf2andfoie grasas models of liver disease
Author:
Sadler Kirsten C.1, Amsterdam Adam1, Soroka Carol2, Boyer James2, Hopkins Nancy1
Affiliation:
1. Center for Cancer Research, Massachusetts Institute of Technology, Cambridge MA 02139, USA 2. Department of Internal Medicine and Yale Liver Center, Yale University School of Medicine, New Haven, CT 06520-8019, USA
Abstract
Hepatomegaly is a sign of many liver disorders. To identify zebrafish mutants to serve as models for hepatic pathologies, we screened for hepatomegaly at day 5 of embryogenesis in 297 zebrafish lines bearing mutations in genes that are essential for embryonic development. Seven mutants were identified, and three have phenotypes resembling different liver diseases. Mutation of the class C vacuolar protein sorting gene vps18results in hepatomegaly associated with large, vesicle-filled hepatocytes,which we attribute to the failure of endosomal-lysosomal trafficking. Additionally, these mutants develop defects in the bile canaliculi and have marked biliary paucity, suggesting that vps18 also functions to traffic vesicles to the hepatocyte apical membrane and may play a role in the development of the intrahepatic biliary tree. Similar findings have been reported for individuals with arthrogryposis-renal dysfunction-cholestasis(ARC) syndrome, which is due to mutation of another class C vps gene. A second mutant, resulting from disruption of the tumor suppressor gene nf2,develops extrahepatic choledochal cysts in the common bile duct, suggesting that this gene regulates division of biliary cells during development and that nf2 may play a role in the hyperplastic tendencies observed in biliary cells in individuals with choledochal cysts. The third mutant is in the novel gene foie gras, which develops large, lipid-filled hepatocytes, resembling those in individuals with fatty liver disease. These mutants illustrate the utility of zebrafish as a model for studying liver development and disease, and provide valuable tools for investigating the molecular pathogenesis of congenital biliary disorders and fatty liver disease.
Publisher
The Company of Biologists
Subject
Developmental Biology,Molecular Biology
Reference67 articles.
1. Amatruda, J. F., Shepard, J. L., Stern, H. M. and Zon, L. I.(2002). Zebrafish as a cancer model system. Cancer Cell1,229-231. 2. Amsterdam, A. and Hopkins, N. (1999). Retrovirus-mediated insertional mutagenesis in zebrafish. Meth. Cell Biol.60,87-98. 3. Amsterdam, A., Burgess, S., Golling, G., Chen, W., Sun, Z.,Townsend, K., Farrington, S., Haldi, M. and Hopkins, N.(1999). A large-scale insertional mutagenesis screen in zebrafish. Genes Dev.13,2713-2724. 4. Amsterdam, A., Nissen, R. M., Sun, Z., Swindell, E. C.,Farrington, S. and Hopkins, N. (2004). Identification of 315 genes essential for early zebrafish development. Proc. Natl. Acad. Sci. USA101,12792-12797. 5. Behrns, K. E., Shaheen, N. J. and Grimm, I. S.(1998). Type I choledochal cyst in association with familial adenomatous polyposis. Am. J. Gastroenterol.93,1377-1379.
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