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

被引：36

作者：

Ishizaki, Hironori ^{[1
,2
]}

Spitzer, Michaela ^{[3
]}

Wildenhain, Jan ^{[3
]}

Anastasaki, Corina ^{[1
,2
]}

Zeng, Zhiqiang ^{[1
,2
]}

Dolma, Sonam ^{[4
]}

Shaw, Michael ^{[5
]}

Madsen, Erik ^{[6
]}

Gitlin, Jonathan ^{[6
]}

Marais, Richard ^{[7
]}

Tyers, Mike ^{[3
,4
]}

Patton, E. Elizabeth ^{[1
,2
]}

机构：

[1] MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland

[2] Univ Edinburgh, Western Gen Hosp, Edinburgh EH4 2XU, Midlothian, Scotland

[3] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland

[4] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ctr Syst Biol, Toronto, ON M5G 1X5, Canada

[5] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England

[6] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37232 USA

[7] Inst Canc Res, Signal Transduct Team, Sect Cell & Mol Biol, London SW3 6JB, England

来源：

DISEASE MODELS & MECHANISMS | 2010年 / 3卷 / 9-10期

基金：

欧洲研究理事会; 美国国家卫生研究院; 英国惠康基金;

关键词：

SACCHAROMYCES-CEREVISIAE GENOME; PEROXISOME BIOGENESIS; BIOACTIVE COMPOUNDS; PARALLEL ANALYSIS; IN-VITRO; METABOLISM; IRON; PATHWAY; COMPLEX; TRANSFORMATION;

D O I：

10.1242/dmm.005769

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：639 / 651

页数：13

共 63 条

[1]

Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors [J].