Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 (gpr126) mutant

eLife

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[1] Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom;Information School, University of Sheffield, Sheffield, United Kingdom;Sosei Heptares, Cambridge, United Kingdom;

关键词: Adgrg6 (Gpr126);    phenotypic screening;    chemoinformatics;    inner ear;    myelination;    adhesion GPCR;    Zebrafish;   

DOI  :  10.7554/eLife.44889

来源: publisher

【 摘 要 】

10.7554/eLife.44889.001Adgrg6 (Gpr126) is an adhesion class G protein-coupled receptor with a conserved role in myelination of the peripheral nervous system. In the zebrafish, mutation of adgrg6 also results in defects in the inner ear: otic tissue fails to down-regulate versican gene expression and morphogenesis is disrupted. We have designed a whole-animal screen that tests for rescue of both up- and down-regulated gene expression in mutant embryos, together with analysis of weak and strong alleles. From a screen of 3120 structurally diverse compounds, we have identified 68 that reduce versican b expression in the adgrg6 mutant ear, 41 of which also restore myelin basic protein gene expression in Schwann cells of mutant embryos. Nineteen compounds unable to rescue a strong adgrg6 allele provide candidates for molecules that may interact directly with the Adgrg6 receptor. Our pipeline provides a powerful approach for identifying compounds that modulate GPCR activity, with potential impact for future drug design.

【 授权许可】

CC BY