Efficient uptake and utilization of iron is essential to normal hematopoiesis. In mammals, dietary iron absorption is carried out by specialized enterocytes in the proximal small intestine. Iron is taken up through the apical transmembrane iron transport, DMT1, Homozygous mutant mice carrying a mutation in DMT1 are severely iron deficient and poorly viable. Until recently, it was not known host iron exists the basolateral surface of the enterocyte to reach the circulation. We recently identified a transmembrane protein, ferroportin1, which as an iron exporter. The ferroportin1 gene is defective in the zebrafish mutant weissherbst. Weissherbst embryos die from severe iron deficiency anemia, resulting from defective iron transport between the yolk sac and the developing embryo. The mammalian ortholog of ferroportin1 is expressed in the basolateral membrane of intestinal enterocytes, and at other sites requiring active iron expert. We hypothesize that ferroportin1 is the basolateral iron transporter in enterocytes and an iron exporter in other cell types In this grant we propose to study the conservation of vertebrate ferroportin1 function and the role of ferroportin1 in vivo. Gene targeting will be used to generate mice lacking ferroportin1 in selected tissues and these animals will be analyzed for defects in iron absorption and homeostasis. Ferroportin1 expression and activity will be analyzed in a panel of mouse mutants with defects in iron metabolism, and in a murine model of human hemochromatosis. Zebrafish studies will investigate the relationship between erythropoiesis and ferroportin1 by studying mRNA expression in known hematopoietic mutants. A mutagenesis screen will also be done to find zebrafish mutants with defects in ferroportin1 mRNA expression. Finally, we plan to do also be done to find zebrafish mutants with defects in ferroportin1 mRNA expression. Finally, we plan to do a suppressor-enhancer screen for ferroportin1 to define factors that genetically coordinate iron metabolism with ferroportin1 in the developing zebrafish embryo. Our findings will improve our understanding of vertebrate iron biology and may be relevant to human patients with iron deficiency and iron overload disorders.
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