Small molecule modifier screen for kit-dependent functions in zebrafish embryonic melanocytes.

Zebrafish is gaining popularity as a vertebrate model for screening small molecules that affect specific phenotypes or genetic pathways. In this study, we present a targeted drug screen to identify drug modifiers of the melanocyte migration defect of a temperature-sensitive allele of the Kit receptor tyrosine kinase, kit(ts). We first test two candidate drugs, the phosphatidylinositol-3-kinase kinase inhibitor (LY294002) and the Erk/MAP kinase inhibitor (PD98059), for their effect on melanocyte migration and survival. We find that LY294002 enhances the migration defect of kit(ts), implicating the phosphatidylinositol-3-kinase kinase pathway in promoting kit-dependent melanocyte migration, but not survival. We then used the kit(ts)-sensitized genetic background to screen a panel of 1280 pharmacologically active drugs to identify drug enhancers and suppressors of the kit(ts) melanocyte migration defect. We identified three drug enhancers of migration, two of which, Papaverine and Isoliquiritigenin, specifically enhance the kit(ts) migration defect, while 8-DPAT affected both melanocyte migration and survival. These drugs now provide additional experimental tools for investigating the mechanisms of kit-promoted melanocyte migration and survival in the zebrafish embryo.