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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/R1474    most recent 00130.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kambe, T. Articles by Andrews, G. K. PubMed PubMed Citation Articles by Kambe, T. Articles by Andrews, G. K.

GENETICALLY MODIFIED ANIMALS AND MODEL ORGANISMS

Slc39a1 to 3 (subfamily II) Zip genes in mice have unique cell-specific functions during adaptation to zinc deficiency

¹Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas; and ²Purdue University Ionomics Facility, Purdue University, West Lafayette, Indiana

Submitted 22 February 2008 ; accepted in final form 17 March 2008

Subfamily II of the solute carrier (Slc)39a family contains three highly conserved members (ZIPs 1–3) that share a 12-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. Here we report that the complete elimination of all three of these Zip genes, by targeted mutagenesis and crossbreeding mice, causes no overt phenotypic effect. When mice were 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, ZIP4 protein in the visceral yolk sac, and initial rates (30 min) of accumulation/retention of ⁶⁷Zn in liver and pancreas. When mice were fed a zinc-deficient diet, embryonic membrane-bound alkaline phosphatase activity was reduced to a much greater extent, and 80% of the embryos of the triple-knockout mice developed abnormally compared with 12% of the embryos of wild-type mice. During zinc deficiency, the accumulation/retention (3 h) of ⁶⁷Zn in the liver and pancreas of weanlings was significantly impaired in the triple-knockout mice compared with 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, noncompensatory roles when this metal is deficient.

pregnancy; stable zinc isotope; triple-knockout mice; zinc homeostasis