title: Chemical screen identifies FDA-approved drugs and target pathways that induce precocious pancreatic endocrine differentiation.
abstract: Pancreatic β-cells are an essential source of insulin and their destruction because of autoimmunity causes type I diabetes. We conducted a chemical screen to identify compounds that would induce the differentiation of insulin-producing β-cells in vivo. To do this screen, we brought together the use of transgenic zebrafish as a model of β-cell differentiation, a unique multiwell plate that allows easy visualization of lateral views of swimming larval fish and a library of clinical drugs. We identified six hits that can induce precocious differentiation of secondary islets in larval zebrafish. Three of these six hits were known drugs with a considerable background of published data on mechanism of action. Using pharmacological approaches, we have identified and characterized two unique pathways in β-cell differentiation in the zebrafish, including down-regulation of GTP production and retinoic acid biosynthesis.
authors.affiliation: Department of Surgery, and McKusick-Nathans Institute for Genetic Medicine, The Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Rovira
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Shamila
authors.initials: S
authors.lastname: Yusuff
authors.forename: Joong Sup
authors.initials: JS
authors.lastname: Shim
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Ferrante
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parsons
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D002109:Caffeic Acids / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017931:DNA Primers / Q000235:genetics; D004121:Dimethyl Sulfoxide; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D004840:Epirizole / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins; D006160:Guanosine Triphosphate / Q000096:biosynthesis; D024243:HMGB1 Protein / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects*; D007814:Larva / Q000187:drug effects; D018613:Microscopy, Confocal; D009173:Mycophenolic Acid / Q000494:pharmacology; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013425:Sulfanilic Acids / Q000494:pharmacology; D014212:Tretinoin / Q000378:metabolism; D015027:Zebrafish; D010128:p-Aminoazobenzene / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000083:Acetanilides; D002109:Caffeic Acids; D017931:DNA Primers; D024243:HMGB1 Protein; C560455:N-(4-(3-(3,4-dihydroxyphenyl)acryloyl)phenyl)-2-(thiophen-2-yl)acetamide; D004364:Pharmaceutical Preparations; D013425:Sulfanilic Acids; D049452:Green Fluorescent Proteins; C007368:C.I. Solvent Yellow 56; D004840:Epirizole; D014212:Tretinoin; D010128:p-Aminoazobenzene; D006160:Guanosine Triphosphate; D009173:Mycophenolic Acid; D004121:Dimethyl Sulfoxide
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