TY - JOUR TI - Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 (gpr126) mutant AU - Diamantopoulou, Elvira AU - Baxendale, Sarah AU - de la Vega de León, Antonio AU - Asad, Anzar AU - Holdsworth, Celia J AU - Abbas, Leila AU - Gillet, Valerie J AU - Wiggin, Giselle R AU - Whitfield, Tanya T A2 - Lyons, David A A2 - Stainier, Didier Y A2 - Raible, David W VL - 8 PY - 2019 DA - 2019/06/10 SP - e44889 C1 - eLife 2019;8:e44889 DO - 10.7554/eLife.44889 UR - https://doi.org/10.7554/eLife.44889 AB - Adgrg6 (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. KW - Adgrg6 (Gpr126) KW - phenotypic screening KW - chemoinformatics KW - inner ear KW - myelination KW - adhesion GPCR JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -