A genetic screen in zebrafish identifies the mutants vps18, nf2 and foie gras as models of liver disease.
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.
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge MA 02139, USA. kristen_sadler_phd98@post.harvard.edu
Kirsten C
KC
Sadler
Adam
A
Amsterdam
Carol
C
Soroka
James
J
Boyer
Nancy
N
Hopkins
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics*; D005820:Genetic Testing; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D006529:Hepatomegaly / Q000235:genetics*; D008107:Liver Diseases / Q000196:embryology / Q000235:genetics*; D009024:Morphogenesis; D009154:Mutation; D025581:Neurofibromin 2 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D033921:Vesicular Transport Proteins; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics*
D017931:DNA Primers; D025581:Neurofibromin 2; C504613:TRAPPC11 protein, zebrafish; D033921:Vesicular Transport Proteins; C504612:Vps18 protein, zebrafish; D029961:Zebrafish Proteins; D044767:Ubiquitin-Protein Ligases