PUBLICATION

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

Authors
Ishizaki, H., Spitzer, M., Wildenhain, J., Anastasaki, C., Zeng, Z., Dolma, S., Shaw, M., Madsen, E., Gitlin, J., Marais, R., Tyers, M., and Patton, E.E.
ID
ZDB-PUB-100820-22
Date
2010
Source
Disease models & mechanisms   3(9-10): 639-651 (Journal)
Registered Authors
Gitlin, Jonathan D., Patton, E. Elizabeth, Zeng, Zhiqiang
Keywords
none
MeSH Terms
  • Animals
  • Butadienes/pharmacology
  • Copper/deficiency
  • Copper/metabolism*
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/metabolism
  • Embryo, Nonmammalian/pathology
  • Gene Knockdown Techniques
  • Genetic Testing*
  • Genome/genetics
  • Melanocytes/drug effects
  • Melanocytes/metabolism*
  • Metabolic Networks and Pathways/drug effects
  • Metabolic Networks and Pathways/genetics
  • Nitriles/pharmacology
  • Phenotype
  • Pigmentation/drug effects
  • Pigmentation/genetics*
  • Saccharomyces cerevisiae/drug effects
  • Saccharomyces cerevisiae/genetics*
  • Zebrafish/embryology
  • Zebrafish/genetics*
PubMed
20713646 Full text @ Dis. Model. Mech.
Abstract
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping