A genetic screen in zebrafish identifies the mutants vps18, nf2 and foie gras as models of liver disease

Kirsten Sadler Edepli, Adam Amsterdam, Carol Soroka, James Boyer, Nancy Hopkins

    Research output: Contribution to journalArticle

    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 vps18 results 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.

    Original languageEnglish (US)
    Pages (from-to)3561-3572
    Number of pages12
    JournalDevelopment
    Volume132
    Issue number15
    DOIs
    StatePublished - Aug 1 2005

    Fingerprint

    Zebrafish
    Hepatomegaly
    Liver Diseases
    Choledochal Cyst
    Hepatocytes
    Fatty Liver
    Mutation
    Genes
    Embryonic Development
    Bile Canaliculi
    Congenital, Hereditary, and Neonatal Diseases and Abnormalities
    Liver
    Essential Genes
    Common Bile Duct
    Biliary Tract
    Protein Transport
    Tumor Suppressor Genes
    Cell Division
    Pathology
    Phenotype

    Keywords

    • Biliary paucity
    • Choledochal cyst
    • Hepatogenesis
    • Hepatomegaly
    • Steatosis
    • Zebrafish

    ASJC Scopus subject areas

    • Molecular Biology
    • Developmental Biology

    Cite this

    Sadler Edepli, K., Amsterdam, A., Soroka, C., Boyer, J., & Hopkins, N. (2005). A genetic screen in zebrafish identifies the mutants vps18, nf2 and foie gras as models of liver disease. Development, 132(15), 3561-3572. https://doi.org/10.1242/dev.01918

    A genetic screen in zebrafish identifies the mutants vps18, nf2 and foie gras as models of liver disease. / Sadler Edepli, Kirsten; Amsterdam, Adam; Soroka, Carol; Boyer, James; Hopkins, Nancy.

    In: Development, Vol. 132, No. 15, 01.08.2005, p. 3561-3572.

    Research output: Contribution to journalArticle

    Sadler Edepli, K, Amsterdam, A, Soroka, C, Boyer, J & Hopkins, N 2005, 'A genetic screen in zebrafish identifies the mutants vps18, nf2 and foie gras as models of liver disease', Development, vol. 132, no. 15, pp. 3561-3572. https://doi.org/10.1242/dev.01918
    Sadler Edepli, Kirsten ; Amsterdam, Adam ; Soroka, Carol ; Boyer, James ; Hopkins, Nancy. / A genetic screen in zebrafish identifies the mutants vps18, nf2 and foie gras as models of liver disease. In: Development. 2005 ; Vol. 132, No. 15. pp. 3561-3572.
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