title: The zebrafish as a model to study polycystic liver disease.
abstract: In the polycystic liver diseases (PLD), genetic defects initiate the formation of cysts in the liver and kidney. In rodent models of PLD (i.e., the PCK rat and Pkd2(WS25/-) mouse), we have studied hepatorenal cystic disease and therapeutic approaches. In this study, we employed zebrafish injected with morpholinos against genes involved in the PLD, including sec63, prkcsh, and pkd1a. We calculated the liver cystic area, and based on our rodent studies, we exposed the embryos to pasireotide [1 μM] or vitamin K3 [100 μM] and assessed the endoplasmic reticulum (ER) in cholangiocytes in embryos treated with 4-phenylbutyrate (4-PBA). Our results show that (a) morpholinos against sec63, prkcsh, and pkd1a eliminate expression of the respective proteins; (b) phenotypic body changes included curved tail and the formation of hepatic cysts in zebrafish larvae; (c) exposure of embryos to pasireotide inhibited hepatic cystogenesis in the zebrafish models; and (d) exposure of embryos to 4-PBA resulted in the ER in cholangiocytes resolving from a curved to a smooth appearance. Our results suggest that the zebrafish model of PLD may provide a means to screen drugs that could inhibit hepatic cystogenesis.
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine , Rochester, MN 55905, USA.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Tietz Bogert
authors.forename: Bing Q
authors.initials: BQ
authors.lastname: Huang
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Gradilone
authors.forename: Tetyana V
authors.initials: TV
authors.lastname: Masyuk
authors.forename: Gary L
authors.initials: GL
authors.lastname: Moulder
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Ekker
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Larusso
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002135:Calcium-Binding Proteins; D003560:Cysts / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D005959:Glucosidases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007814:Larva / Q000378:metabolism; D008107:Liver Diseases / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D060172:Morpholinos / Q000008:administration & dosage / Q000378:metabolism; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000627:therapeutic use; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism; D024483:Vitamin K 3 / Q000008:administration & dosage / Q000627:therapeutic use; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D004265:DNA Helicases; D005959:Glucosidases; D047908:Intracellular Signaling Peptides and Proteins; D060172:Morpholinos; D010654:Phenylbutyrates; D013004:Somatostatin; D050396:TRPP Cation Channels; D024483:Vitamin K 3; C075773:4-phenylbutyric acid; C517782:pasireotide; C070368:PRKCSH protein, human; C518881:HFM1 protein, human