Generation and Characterization of Mice Lacking the Zinc Uptake Transporter ZIP3

Abstract

The mouse ZIP3 (SLC39A3) gene encodes an eight-transmembrane-domain protein that has been conserved in mammals and can function to transport zinc. To analyze the expression of ZIP3 in the early embryo and neonate and to determine its in vivo function, we generated ZIP3 null mice in which the ZIP3 open reading frame was replaced with that of the enhanced green fluorescent protein (EGFP) reporter. EGFP fluorescence revealed that ZIP3 was expressed in the inner cell mass of the blastocyst and later during embryonic development in many tissues. Elevated expression was apparent in the embryonic brain and neurotube and neonatal gonads. Homozygous knockout mice were viable and fertile and under normal growth conditions exhibited no obvious phenotypic abnormalities. Deletion of ZIP3 did not alter zinc homeostasis at the molecular level as assessed by essential metal levels and the expression of zinc-responsive genes. In knockout mice stressed with a zinc-deficient diet during pregnancy or at weaning, a subtle increase in the sensitivity to abnormal morphogenesis of the embryo and to depletion of thymic pre-T cells, respectively, was noted. These results suggest that this protein plays an ancillary role in zinc homeostasis in mice.

Novel zinc-responsive post-transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5)

“…Zinc demands also increase during pregnancy coincident with the rapid growth and differentiation of the embryo. Embryos in pregnant mice fed a ZnD diet beginning on d8 of pregnancy have a greatly increased risk of abnormal development (Dufner-Beattie et al, 2005. As noted previously (Dufner-Beattie et al, 2003b, Zip4 mRNA abundance was significantly increased in the maternal intestine and fetal VYS in mice fed the ZnD diet, while Zip5 and Zip1 mRNA abundance were unaltered (Figure 3).…”

“…In mammals, most of the ZIP proteins fall into one of two subfamilies, named subfamily II (3 members) and LIV-1 (9 members). Studies of knockout mice revealed that the members of subfamily II are particularly important when dietary zinc becomes limiting (Dufner-Beattie et al, 2005Peters et al, 2007). Less is known about the physiological functions of most LIV-1 family members.…”

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

“…Knockout mice with ZIP1 and/or ZIP3 deletions also have no apparent phenotype unless dietary zinc becomes limiting (Dufner-Beattie et al, 2005. Therefore, the effect of dietary zinc deficiency on Zip2-knockout mice was examined using several experimental protocols.…”

Systematic functional characterization of putative zinc transport genes and identification of zinc toxicosis phenotypes inDrosophila melanogaster

“…As a result, homozygous lm/lm pups suckling from lm/lm dams do not survive past the first 2weeks of neonatal development (Murgia et al, 2006). Mice with impaired ZIP1, ZIP2 or ZIP3 function display a decreased ability to absorb zinc from the diet, particularly during pregnancy when zinc absorption is normally increased (Dufner-Beattie et al, 2005;Dufner-Beattie et al, 2006). The ZnT8 knockout (KO) mouse model, which displays decreased insulin secretion, has provided insights into the endogenous function of ZnT8 as an importer of zinc into insulin-containing granules in pancreatic -cell islets (Hardy et al, 2011).…”