The overall long-term objective of our studies is to elucidate the molecular mechanisms involved in zinc homeostasis in mammals. Specifically, we have been studying the Zip4 gene, mutations in which cause the rare, autosomal recessive trait acrodermatitis enteropathica (AE), in humans. ZIP4 is a member of the solute carrier 39a superfamily of metal transporters, and we find that ZIP5 is a close relative. In this competing continuation, we propose to test the hypothesis that ZIP4 and ZIP5 both play central physiological roles in zinc homeostasis with ZIP4 being the major mechanism for uptake of limiting dietary zinc while ZIP5 plays a major role in the removal of zinc under zinc-replete conditions. The hypothesis that these proteins have opposing functions is based on our finding that they localize to opposite membranes of polarized intestinal enterocytes and visceral endoderm cells, cell-types critical for proper zinc homeostasis, and they show opposite responses to zinc availability in these cells. In the initial funding period we discovered that mouse Zip4 mRNA expression and ZIP4 and ZIP5 proteins are dynamically regulated by several novel posttranscriptional and opposing zinc-dependent mechanisms. We also discovered that the mouse Zip4 gene is essential for early embryonic development and that haploinsufficiency exerts pleiotropic effects on the development of several organ systems and causes hypersensitivity to dietary zinc deficiency. Thus, Zip4 is a critically important gene that warrants further investigation. There are no genetic data on ZIP5 function but its zinc-dependent regulation opposite to that of ZIP4 suggests that it may be very important. To further address the functions and mechanisms of regulation of these zinc transporters we will pursue the following specific aims: 1) Determine the effects of tissue-specific conditional knockouts of the Zip4 and/or Zip5 genes on zinc homeostasis in the mouse, and 2) Explore the zinc-dependent mechanisms of posttranscriptional zinc-regulation of ZIP4 and ZIP5. These studies will contribute to our understanding of the lethal human genetic disorder acrodermatitis enteropathica and provide important insights into the etiology of several birth defects, as well as contribute to our basic understanding of the molecular mechanisms governing mammalian zinc homeostasis.

Public Health Relevance

These studies will contribute to our understanding of the lethal human genetic disorder called acrodermatitis enteropathica (AE). Understanding the molecular mechanisms that underlie this disease will also provide important insights into the etiology of several birth defects that we discovered to be associated with mutations of the AE gene in mice. In a global sense, these studies will contribute to our basic understanding of the molecular mechanisms governing the homeostasis of the essential metal zinc in mammals.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Maruvada, Padma
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University of Kansas
Schools of Medicine
Kansas City
United States
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Geiser, Jim; De Lisle, Robert C; Finkelstein, David et al. (2013) Clioquinol synergistically augments rescue by zinc supplementation in a mouse model of acrodermatitis enteropathica. PLoS One 8:e72543
Weaver, Benjamin P; Andrews, Glen K (2012) Regulation of zinc-responsive Slc39a5 (Zip5) translation is mediated by conserved elements in the 3'-untranslated region. Biometals 25:319-35
Weaver, Benjamin P; Zhang, Yuxia; Hiscox, Stephen et al. (2010) Zip4 (Slc39a4) expression is activated in hepatocellular carcinomas and functions to repress apoptosis, enhance cell cycle and increase migration. PLoS One 5:
Belloni-Olivi, Luisa; Marshall, Cathleen; Laal, Bachchu et al. (2009) Localization of zip1 and zip4 mRNA in the adult rat brain. J Neurosci Res 87:3221-30
Kambe, Taiho; Andrews, Glen K (2009) Novel proteolytic processing of the ectodomain of the zinc transporter ZIP4 (SLC39A4) during zinc deficiency is inhibited by acrodermatitis enteropathica mutations. Mol Cell Biol 29:129-39
Kelleher, Shannon L; Lopez, Veronica; Lonnerdal, Bo et al. (2009) Zip3 (Slc39a3) functions in zinc reuptake from the alveolar lumen in lactating mammary gland. Am J Physiol Regul Integr Comp Physiol 297:R194-201
Andrews, Glen K (2008) Regulation and function of Zip4, the acrodermatitis enteropathica gene. Biochem Soc Trans 36:1242-6
Kambe, Taiho; Weaver, Benjamin P; Andrews, Glen K (2008) The genetics of essential metal homeostasis during development. Genesis 46:214-28
Weaver, Benjamin P; Dufner-Beattie, Jodi; Kambe, Taiho et al. (2007) Novel zinc-responsive post-transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5). Biol Chem 388:1301-12
Dufner-Beattie, Jodi; Weaver, Benjamin P; Geiser, Jim et al. (2007) The mouse acrodermatitis enteropathica gene Slc39a4 (Zip4) is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency. Hum Mol Genet 16:1391-9

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