Targeting of the mouse Slc39a2 (Zip2) gene reveals highly cell‐specific patterns of expression, and unique functions in zinc, iron, and calcium homeostasis

Abstract

Fourteen members of the Slc39a superfamily of metal ion uptake transporters have been identified in mice and humans, but the physiological functions of most remain obscure. Herein, we created mice with Zip2 (Slc39a2) genes in which the open reading frame was replaced with that of the enhanced green fluorescent protein (EGFP), to study temporal and spatial patterns of Zip2 gene expression and examine the physiological roles of this transporter. Expression of this gene was remarkably cell-type specific and developmentally regulated in pericentral hepatocytes, developing keratinocytes, and a subset of immature dendritic cells in the immune system. In addition, the Zip2 gene was transiently expressed in giant trophoblast cells in the placenta. Although the Zip2 gene was not essential under conditions of normal dietary zinc, it played an important role in adapting to dietary zinc deficiency during pregnancy, and in the homeostasis of iron in the liver as well as iron and calcium in developing embryos. These studies suggest that active expression of the Zip2 gene in these few specific cell types, aforementioned, plays a particularly important role during zinc deficiency. These studies further reveal novel interactions between zinc transporter function and the homeostasis of other essential metals.

ZIP2 Protein, a Zinc Transporter, Is Associated with Keratinocyte Differentiation

“…Scale bars ϭ 50 m. knockout mice exhibit skin blistering during early embryogenesis. However, the underlying mechanism for this remains unknown (24). Considering the results of our study, it is likely that Zip2 knockout mice developed a deficiency in the skin because of the abnormal differentiation of keratinocytes.…”

ZIP8 Is an Iron and Zinc Transporter Whose Cell-surface Expression Is Up-regulated by Cellular Iron Loading

“…In initial screens of the remaining 12 ZIP family members, we have evidence that only one of these, ZIP2, appears capable of transporting iron. 3 Interestingly, previous studies of the Zip2 knock-out mouse concluded that ZIP2 plays a role in iron homeostasis (53). In an effort to identify which of the 14 ZIP family members might transport iron, we previously examined the effect of iron deficiency and iron overload on the expression of all the ZIP proteins in rat liver (22).…”

Novel Proteolytic Processing of the Ectodomain of the Zinc Transporter ZIP4 (SLC39A4) during Zinc Deficiency Is Inhibited by Acrodermatitis Enteropathica Mutations

“…Chelex-treated FBS was filter sterilized, aliquoted, and stored at Ϫ80°C. Metal concentrations were measured by inductively coupled plasma mass spectrometry (7,21). DMEM or DMEM/F-12 was adjusted to 10% or 5%, respectively, with Chelex-treated FBS, which restored all the essential metals to near normal concentrations except for zinc, which was reduced about 100-fold.…”