Identification of compounds that rescue otic and myelination defects in the zebrafish <i>adgrg6</i> (<i>gpr126</i>) mutant.

Abstract

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 <i>adgrg6</i> also results in defects in the inner ear: otic tissue fails to down-regulate <i>versican</i> 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 <i>versican b</i> expression in the <i>adgrg6</i> mutant ear, 41 of which also restore <i>myelin basic protein</i> gene expression in Schwann cells of mutant embryos. Nineteen compounds unable to rescue a strong <i>adgrg6</i> 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.