title: First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass.
abstract: Whole-organism chemical screening can circumvent bottlenecks that impede drug discovery. However, in vivo screens have not attained throughput capacities possible with in vitro assays. We therefore developed a method enabling in vivo high-throughput screening (HTS) in zebrafish, termed automated reporter quantification in vivo (ARQiv). In this study, ARQiv was combined with robotics to fully actualize whole-organism HTS (ARQiv-HTS). In a primary screen, this platform quantified cell-specific fluorescent reporters in &gt;500,000 transgenic zebrafish larvae to identify FDA-approved (Federal Drug Administration) drugs that increased the number of insulin-producing β cells in the pancreas. 24 drugs were confirmed as inducers of endocrine differentiation and/or stimulators of β-cell proliferation. Further, we discovered novel roles for NF-κB signaling in regulating endocrine differentiation and for serotonergic signaling in selectively stimulating β-cell proliferation. These studies demonstrate the power of ARQiv-HTS for drug discovery and provide unique insights into signaling pathways controlling β-cell mass, potential therapeutic targets for treating diabetes.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, United States.
authors.forename: Guangliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, United States.
authors.forename: Surendra K
authors.initials: SK
authors.lastname: Rajpurohit
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, United States.
authors.forename: Fabien
authors.initials: F
authors.lastname: Delaspre
authors.affiliation: Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, United States.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Walker
authors.affiliation: Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, United States.
authors.forename: David T
authors.initials: DT
authors.lastname: White
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, United States.
authors.forename: Alexis
authors.initials: A
authors.lastname: Ceasrine
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, United States.
authors.forename: Rejji
authors.initials: R
authors.lastname: Kuruvilla
authors.affiliation: Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, United States.
authors.forename: Ruo-Jing
authors.initials: RJ
authors.lastname: Li
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau, China.
authors.forename: Joong S
authors.identifier: http://orcid.org/0000-0003-0167-7307
authors.initials: JS
authors.lastname: Shim
authors.affiliation: Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, United States.
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parsons
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, United States.
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Mumm
mesh_terms: D000818:Animals; D057205:Automation, Laboratory / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D055808:Drug Discovery / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D015027:Zebrafish / Q000502:physiology*
keywords: NF-κB; beta cell; cell biology; developmental biology; diabetes; high-throughput screening; mouse; serotonin; stem cells; whole-organism drug discovery; zebrafish