Combined zebrafish-yeast chemical-genetic screens reveal gene - Copper-nutrition interactions that modulate melanocyte pigmentation

Hironori Ishizaki, Michaela Spitzer, Jan Wildenhain, Corina Anastasaki, Zhiqiang Zeng, Sonam Dolma, Michael Shaw, Erik Madsen, Jonathan Gitlin, Richard Marais, Mike Tyers, Elizabeth E. Patton

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


Hypopigmentation is a feature of copper deficiency in humans, as caused by mutation of the copper (Cu2+) 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.

Original languageEnglish
Pages (from-to)639-651
Number of pages13
JournalDMM Disease Models and Mechanisms
Issue number9-10
StatePublished - Sep 2010


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