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WIREs Dev Biol
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Small molecule screening in zebrafish: swimming in potential drug therapies

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Abstract Phenotype‐driven chemical genetic screens in zebrafish have become a proven approach for both dissection of developmental mechanisms and discovery of potential therapeutics. A library of small molecules can be arrayed into multiwell plates containing zebrafish embryos. The embryo becomes a whole organism in vivo bioassay that can produce a phenotype upon treatment. Screens have been performed that are based simply on the morphology of the embryo. Other screens have scored complex phenotypes using whole mount in situ hybridization, fluorescent transgenic reporters, and even tracking of embryo movement. The availability of many well‐characterized zebrafish mutants has also enabled the discovery of chemical suppressors of genetic phenotypes. Importantly, the application of chemical libraries that already contain FDA‐approved drugs has allowed the rapid translation of hits from zebrafish chemical screens to clinical trials. WIREs Dev Biol 2012, 1:459–468. doi: 10.1002/wdev.37 This article is categorized under: Technologies > Perturbing Genes and Generating Modified Animals

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(a) A target‐based chemical screen. (i) A protein of interested is selected. (ii) High‐throughput screening is used to find a small molecule that produces a positive result in a bioassay. (iii) The compound must be tested to determine if it produces a desired phenotype in vivo—in this example zebrafish embryos are treated. (b) A phenotype‐based chemical screen. (i) Zebrafish embryos are arrayed in multiwell plates containing compounds from a library. Stage‐matched wild‐type embryos (left) are compared to those with a phenotype (right). (ii) The small molecule that produces the phenotype is retrieved from the library and retested. (iii) The protein target and mechanism of action must be determined.

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Zebrafish mass breeding vessel. (a) The three primary components of the breeding vessel. (b) Framework of the bottom or ‘floor’ of the spawning platform, showing variation in topography. (c) The breeding vessel, with all three primary components engaged and ready for operation. (Reprinted with permission from Ref 32. Copyright 2011 PLoS ONE)

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BCI structure–activity relationship studies. (a–d) Lateral views of 30 h.p.f. Tg(dusp6:EGFP) embryos treated with dimethyl sulfoxide (DMSO) (a), BCI (b), BI (c), and ICD (d). GFP fluorescence was enhanced in BCI‐treated embryos (b), whereas related analogs, shown in inner panels, had no effect, even at fourfold higher concentrations (c,d). Red arrowheads mark the mid‐hindbrain boundary. Scale bar, 250 µM. (Adapted with permission from Ref 29. Copyright 2009 Macmillan Publishers Ltd.)

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Dorsomorphin (DM) induces dorsalization in zebrafish embryos. (a) Structure of DM. (b) Vehicle‐treated wild‐type zebrafish embryo 36 h.p.f. Ventral tail fin is highlighted in brackets. (c) Zebrafish embryo treated with 10 µM DM at 6–8 h.p.f. and photographed at 36 h.p.f. (d) Zebrafish embryos treated with 10 µM DM at 6 h.p.f. occasionally develop ectopic tails (*) at 48 h.p.f. (e) Embryos treated with 10 µM DM at 1–2 h.p.f. show severe dorsalization at 48 h.p.f. Embryos (b–e) are shown on lateral view. (Adapted with permission from Ref 28. Copyright 2008 Macmillan Publishers Ltd.)

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