Molecular Biology of Mammalian Zinc Homeostasis

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The overall long-term objective of these studies is to elucidate the molecular mechanisms involved in zinc homeostasis in mice during pregnancy and embryonic development. Zinc deficiency profoundly affects reproductive processes and jeopardizes embryonic development, yet little is known about how zinc homeostasis is maintained. Specifically, we will study genes which encode zinc transporters. We will focus on three recently identified members of the mouse ZIP gene superfamily of metal transporters. Mouse ZIP1, 2 and 3 are closely related to each other and to recently identified human zinc transporters of the ZIP superfamily. These ZIP genes are responsible for zinc uptake and similar zinc transporters are up-regulated by zinc deficiency and display cell-specific expression in lower eukaryotes. The molecular biology of these mZIP genes in the reproductive tract and embryo will be examined. We will test the hypothesis that these zinc transporters play a central physiological role in zinc homeostasis in mammals. Therefore, the specific aims of this revised proposal are to; 1) clone and characterize these mouse ZIP genes and cDNAs, and examine their transport properties; 2) delineate the temporal-spatial patterns of expression of these mZIP genes in maternal and embryonic tissues, and examine their regulation by dietary zinc, and 3) determine the affects of targeted mutations of these mZIP genes on zinc homeostasis. This project represents a collaborative effort between the laboratories of Drs. Andrews, Eide and Palmiter. The P.I., Dr. Andrews is an expert in mammalian embryonic development and zinc deficiency, and in the molecular biology of metallothionein gene regulation. The co-I., Dr. Eide is an expert and leader in the field of ZIP transport function, and our collaborator, Dr. Palmiter is an expert in gene targeting in mice.