Slc39a1 to 3 (subfamily II) Zip genes in mice have unique cell-specific functions during adaptation to zinc deficiency.
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 (67)Zn 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 (67)Zn 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.
Kambe
Taiho
T
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160-7421, USA.
Geiser
Jim
J
Lahner
Brett
B
Salt
David E
DE
Andrews
Glen K
GK
D000222:Adaptation, Physiological / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000235:genetics* / Q000502:physiology*; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D004032:Diet; D053595:Embryonic Stem Cells / Q000502:physiology; D005260:Female; D005822:Genetic Vectors / Q000502:physiology; D006706:Homeostasis; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014131:Trace Elements / Q000378:metabolism; D015032:Zinc / Q000172:deficiency* / Q000378:metabolism*; D015037:Zinc Radioisotopes
D027682:Cation Transport Proteins; C485744:Slc39a1 protein, mouse; C498425:Slc39a2 protein, mouse; C498426:Slc39a3 protein, mouse; D014131:Trace Elements; D015037:Zinc Radioisotopes; D007501:Iron; D015032:Zinc