A novel missense mutation in the proprotein convertase gene furinb causes hepatic cystogenesis during liver development in zebrafish
A novel missense mutation in the proprotein convertase gene furinb causes hepatic cystogenesis during liver development in zebrafish
Abstract Hepatic cysts are fluid-filled lesions in the liver that are estimated to occur in 5% of the population. They may cause hepatomegaly and abdominal pain. Progression to secondary fibrosis, cirrhosis, or cholangiocarcinoma can lead to morbidity and mortality. Previous studies of patients and rodent models have associated hepatic cyst formation with increased proliferation and fluid secretion in cholangiocytes, which are partially due to impaired primary cilia. Congenital hepatic cysts are thought to originate from faulty bile duct development, but the underlying mechanisms are not fully understood. In a forward genetic screen, we identified a zebrafish mutant that develops hepatic cysts during larval stages. Cyst formation in these mutants is not due to changes in biliary cell proliferation, bile secretion, or impairment of primary cilia. Instead, time-lapse live imaging data showed that the mutant biliary cells failed to form interconnecting bile ducts because of defects in motility and protrusive activity. Accordingly, immunostaining revealed an excessive and disorganized actin and microtubule cytoskeleton in the mutant biliary cells. By whole-genome sequencing, we determined that the cystic phenotype in the mutant was caused by a missense mutation in the furinb gene which encodes a proprotein convertase. The mutation alters Furinb localization and causes endoplasmic reticulum (ER) stress. The cystic phenotype could be suppressed by treatment with the ER stress inhibitor 4-phenylbutyric acid and exacerbated by treatment with the ER stress inducer tunicamycin. The mutant livers also exhibited increased mTOR signaling and treatment with the mTOR inhibitor rapamycin partially blocked cyst formation by reducing ER stress. Our study has established a novel vertebrate model for studying hepatic cystogenesis and illustrated the role of ER stress in the disease pathogenesis.
Liu Jiandong、Lin Xueying、Fourman Makenzie N.、Ninov Nikolay、Fiddes Ian、Delous Marion、Ellis Jillian L.、Vanhollebeke Benoit、Yin Chunyue、Otis Jessica P.、Houvras Yariv、Farber Steven A.、Xu Xiaolei、Stainier Didier Y.R.、Zhang Changwen、Evason Kimberley J.
Department of Biochemistry and Biophysics, Program in Developmental and Stem Cell Biology, Liver Center and Diabetes Center, University of California San Francisco||McAllister Heart Institute, Department of Pathology and Laboratory Medicine, School of Medicine, the University of North Carolina at Chapel HillDepartment of Biochemistry and Molecular Biology, Department of Cardiovascular MedicineDivision of Gastroenterology, Hepatology and Nutrition, Cincinnati Children?ˉs Hospital Medical CenterDepartment of Biochemistry and Biophysics, Program in Developmental and Stem Cell Biology, Liver Center and Diabetes Center, University of California San Francisco||Centre for Regenerative Therapies TU Dresden||Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus of TU Dresden, German Center for Diabetes Research (DZD e.V.)Department of Biochemistry and Biophysics, Program in Developmental and Stem Cell Biology, Liver Center and Diabetes Center, University of California San FranciscoDepartment of Biochemistry and Biophysics, Program in Developmental and Stem Cell Biology, Liver Center and Diabetes Center, University of California San Francisco||Equipe GENDEV, Centre de Recherche en Neurosciences de Lyon, Inserm U1028, CNRS UMR5292, Universite Lyon 1Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children?ˉs Hospital Medical CenterDepartment of Biochemistry and Biophysics, Program in Developmental and Stem Cell Biology, Liver Center and Diabetes Center, University of California San Francisco||Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Universite libre de Bruxelles (ULB)Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children?ˉs Hospital Medical Center||Department of Biochemistry and Biophysics, Program in Developmental and Stem Cell Biology, Liver Center and Diabetes Center, University of California San Francisco||Division of Developmental Biology, Cincinnati Children?ˉs Hospital Medical CenterDepartment of Embryology, Carnegie Institution for Science||Department of Biology, Johns Hopkins University||Department of Molecular and Cellular Biology and Biochemistry, Brown UniversityWeill Cornell Medical College and New York Presbyterian HospitalDepartment of Embryology, Carnegie Institution for Science||Department of Biology, Johns Hopkins UniversityDepartment of Biochemistry and Molecular Biology, Department of Cardiovascular MedicineDepartment of Biochemistry and Biophysics, Program in Developmental and Stem Cell Biology, Liver Center and Diabetes Center, University of California San Francisco||Max Planck Institute for Heart and Lung Research, Department of Developmental GeneticsDivision of Gastroenterology, Hepatology and Nutrition, Cincinnati Children?ˉs Hospital Medical CenterDepartment of Biochemistry and Biophysics, Program in Developmental and Stem Cell Biology, Liver Center and Diabetes Center, University of California San Francisco||Huntsman Cancer Institute and Department of Pathology, University of Utah
基础医学生物科学研究方法、生物科学研究技术生理学
Liu Jiandong,Lin Xueying,Fourman Makenzie N.,Ninov Nikolay,Fiddes Ian,Delous Marion,Ellis Jillian L.,Vanhollebeke Benoit,Yin Chunyue,Otis Jessica P.,Houvras Yariv,Farber Steven A.,Xu Xiaolei,Stainier Didier Y.R.,Zhang Changwen,Evason Kimberley J..A novel missense mutation in the proprotein convertase gene furinb causes hepatic cystogenesis during liver development in zebrafish[EB/OL].(2025-03-28)[2025-05-04].https://www.biorxiv.org/content/10.1101/2022.02.24.481764.点此复制
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