Hypopigmentation is a feature of
copper deficiency in humans, as caused by mutation of the
copper (Cu(2+)) transporter ATP7A in
Menkes disease, or an inability to absorb
copper after gastric surgery. However, many causes of
copper deficiency are unknown, and genetic polymorphisms might underlie sensitivity to suboptimal environmental
copper conditions. Here, we combined phenotypic screens in zebrafish for compounds that affect
copper metabolism with yeast chemical-genetic profiles to identify pathways that are sensitive to
copper depletion. Yeast chemical-genetic interactions revealed that defects in intracellular trafficking pathways cause sensitivity to low-
copper conditions; partial knockdown of the analogous Ap3s1 and Ap1s1 trafficking components in zebrafish sensitized developing melanocytes to
hypopigmentation in low-
copper environmental conditions. Because trafficking pathways are essential for
copper loading into cuproproteins, our results suggest that hypomorphic alleles of trafficking components might underlie sensitivity to reduced-
copper nutrient conditions. In addition, we used zebrafish-yeast screening to identify a novel target pathway in
copper metabolism for the small-molecule
MEK kinase inhibitor
U0126. The zebrafish-yeast screening method combines the power of zebrafish as a disease model with facile genome-scale identification of chemical-genetic interactions in yeast to enable the discovery and dissection of complex multigenic interactions in disease-gene networks.