ZFIN ID: ZDB-PUB-150729-3
First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass
Wang, G., Rajpurohit, S.K., Delaspre, F., Walker, S.L., White, D.T., Ceasrine, A., Kuruvilla, R., Li, R.J., Shim, J.S., Liu, J.O., Parsons, M.J., Mumm, J.S.
Date: 2015
Source: eLIFE 4: (Journal)
Registered Authors: Delaspre, Fabien, Mumm, Jeff, Rajpurohit, Surendra, Walker, Steven, Wang, Guangliang
Keywords: NF-κB, beta cell, cell biology, developmental biology, diabetes, high-throughput screening, mouse, serotonin, stem cells, whole-organism drug discovery, zebrafish
MeSH Terms: Animals; Automation, Laboratory/methods; Cell Differentiation/drug effects*; Cell Proliferation/drug effects*; Drug Discovery/methods* (all 9) expand
PubMed: 26218223 Full text @ Elife
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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). Here, 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 >500,000 transgenic zebrafish larvae to identify FDA-approved drugs that increased the number of insulin-producing β cells in the pancreas. Twenty-four 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.
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