Submitted on February 22, 2008
Accepted on March 17, 2008
Slc39a1 to 3 (Subfamily II) Zip Genes in Mice have Unique Cell-Specific Functions during Adaptation to Zinc Deficiency
Taiho Kambe1, Jim Geiser1, Brett Lahner2, David E. Salt2, and Glen K. Andrews1*
1 Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, United States
2 Purdue University Ionomics Facility, Purdue University, West Lafayette, Indiana, United States
* To whom correspondence should be addressed. E-mail: gandrews{at}kumc.edu.
Subfamily II of the solute-carrier (Slc)39a family contains three highly conserved members (ZIPs 1 to 3) that share a twelve amino acid signature sequence present in the putative fourth transmembrane domain and function as zinc transporters in transfected cells. The physiological significance of this genetic redundancy is unknown. Herein, we report that the complete elimination of all three of these Zip genes, by targeted mutagenesis and cross-breeding mice, causes no overt phenotypic effect. When fed a zinc-adequate diet, several indicators of zinc status were indistinguishable between wild-type and triple-knockout mice; including embryonic morphogenesis and growth, alkaline phosphatase activity in the embryo, and ZIP4 protein in the visceral yolk sac and initial rates (30 min) of accumulation/retention of 67Zn in liver and pancreas. When fed a zinc-deficient diet, embryonic membrane-bound alkaline phosphatase activity was reduced to a much greater extent and 80% of the embryos in the triple-knock mice developed abnormally compared to 12% of the embryos in wild-type mice. During zinc deficiency, the accumulation/retention (3 hr) of 67Zn in the liver and pancreas of weanlings was significantly impaired in the triple-knockout mice compared to wild-type mice. Thus, none of these three mammalian Zip genes apparently plays a critical role in zinc homeostasis when zinc is replete, but they play important, non-compensatory roles when this metal is deficient.
