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Figure 2

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ZDB-FIG-230711-22

Publication

Lescouzères et al., 2023 - A multilevel screening pipeline in zebrafish identifies therapeutic drugs for GAN

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Figure 2

Development of a screening strategy in zebrafish to score, categorize, and refine candidates to 103 hits

Efficacy of Hits is determined by the establishment of a z‐score scale, ranging from 0 (noninjected “WT Control,” green) to negative values < −2 (gan morpholino‐injected “MO Control,” red) after normalization with WT values. Representative pictures of video tracking show the total distance traveled over 1 h by quadruplicate WT and MO fish at 5 dpf.

Primary screening on gan morphants identifies four chemicals classes depending on their mean z‐scores and individual values. Hits restore motility in > 2/4 animals (min 2 individual z‐scores > −1), while non‐Hits may have an effect only on 1/4 animals (max 1 z‐score > −1) and toxic compounds induce death in ≥ 3 fish. Hits are further categorized in two groups A and B, accordingly to the penetrance of the phenotype: B Hits exhibit a negative mean z‐scores due to 1–2 fish with low values, while A Hits are penetrant with positive mean z‐scores. Screening of the 1,280 Prestwick Chemical compounds identifies 809 Toxic and 368 Non‐Hits molecules, and a total of 103 Hits with 71 A Hits and 32 B Hits.

Summary of the screening strategy workflow for the GAN disease, encompassing behavioral tests in the two gan zebrafish models (Screen and Rescreen), computational approach using System Biology (Filter I) and a novel imaging screening methodology at the cellular level in zebrafish (Filters II 1–3).

Expression Data

Expression Detail

Antibody Labeling

Phenotype Data

Phenotype Detail

Acknowledgments

This image is the copyrighted work of the attributed author or publisher, and ZFIN has permission only to display this image to its users. Additional permissions should be obtained from the applicable author or publisher of the image. Full text @ EMBO Mol. Med.