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Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter

Abstract

Defects in iron absorption and utilization lead to iron deficiency and overload disorders. Adult mammals absorb iron through the duodenum, whereas embryos obtain iron through placental transport. Iron uptake from the intestinal lumen through the apical surface of polarized duodenal enterocytes is mediated by the divalent metal transporter, DMT1 (refs 1,2,3). A second transporter has been postulated to export iron across the basolateral surface to the circulation. Here we have used positional cloning to identify the gene responsible for the hypochromic anaemia of the zebrafish mutant weissherbst. The gene, ferroportin1, encodes a multiple-transmembrane domain protein, expressed in the yolk sac, that is a candidate for the elusive iron exporter. Zebrafish ferroportin1 is required for the transport of iron from maternally derived yolk stores to the circulation and functions as an iron exporter when expressed in Xenopus oocytes. Human Ferroportin1 is found at the basal surface of placental syncytiotrophoblasts, suggesting that it also transports iron from mother to embryo. Mammalian Ferroportin1 is expressed at the basolateral surface of duodenal enterocytes and could export cellular iron into the circulation. We propose that Ferroportin1 function may be perturbed in mammalian disorders of iron deficiency or overload.

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Acknowledgements

We thank J. Amatruda, C. Trenor, V. Sellers and J. Levy for critical review of this manuscript; P. Haffter and C. Nusslein-Volhard for providing the zebrafish blood mutants before publication; C. Amemiya, J. Postlethwait, D. Nathan, A. Oates and J. Best for helpful discussions and experimental advice; D. Giarla for administrative assistance; B. Hogan, J. Rossant and L. Solnica-Krezel for discussions on placental and yolk sac biology; and L. Kunkel, G. Gilliland and W. Talbot for support and advice. L.I.Z. and N.C.A. are Associate Investigators of the Howard Hughes Medical Institute. This work was supported by grants from the NIH.

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Correspondence to Leonard I. Zon.

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Further reading

Figure 1: Phenotypic analysis of weissherbst (weh) mutants.
Figure 2: Positional cloning of the weissherbst gene.
Figure 3: Developmental expression of Ferroportin1 and phenotypic rescue of weh embryos.
Figure 4: Ferroportin1 expression in human and mouse tissues.

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