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

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 also results in defects in the inner ear: otic tissue fails to down-regulate 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 expression in the mutant ear, 41 of which also restore gene expression in Schwann cells of mutant embryos. Nineteen compounds unable to rescue a strong 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.