Compartmentalized zinc deficiency and toxicities caused by ZnT and Zip gene over expression result in specific phenotypes in Drosophila

Movement of zinc ions across cellular membranes is achieved mainly by two families of zinc transport genes encoding multi-transmembrane domain proteins. Members of the Zip family generally transport zinc into the cytosol, either from outside the cell or from the lumen of subcellular organelles such as the endoplasmic reticulum, Golgi, endosomes or storage vacuoles. ZnT proteins move zinc in the opposite direction, resulting in efflux from the cell or uptake into organelles. Zinc homeostasis at both the cellular and systemic level is achieved by the coordinated action of numerous Zip and ZnT proteins, twenty-four in mammals and seventeen in the vinegar fly Drosophila melanogaster. Previously, we have identified a zinc toxicity phenotype in the Drosophila eye, caused by targeted over expression of dZip42C.1 (dZip1) combined with knockdown of dZnT63C (dZnT1). In general, this phenotype was rescued by increased zinc efflux or decreased uptake and was exacerbated by decreased efflux or increased uptake. Now we have identified three additional zinc dyshomeostasis phenotypes caused by over expression of dZnT86D, dZnT86DeGFP and dZip71BFLAG. Genetic and dietary manipulation experiments showed that these three phenotypes all differ both from each other and from our original zinc toxicity phenotype. Based on these data and the approximate subcellular localization of each zinc transport protein, we propose that each phenotype represents a different redistribution of zinc within these cells, resulting in a Golgi zinc toxicity, a Golgi zinc deficiency and a combined Golgi/other organelle zinc toxicity respectively. We are able to group the remaining Drosophila Zip and ZnT genes into several functional categories based on their interaction with the three novel zinc dyshomeostasis phenotypes, allowing the role of each zinc transport protein to be defined in greater detail. This research highlights the differential effects that redistribution of zinc can have within a particular tissue and identifies the Golgi as being particularly sensitive to both excess and insufficient zinc.