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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Fleming,M. D. et al. Microcytic anemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nature Genet. 16, 383–386 (1997).
Gunshin,H. et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388, 482– 488 (1997).
Andrews,N. C. Disorders of iron metabolism. N. Engl. J. Med. 341, 1986–1995 (1999).
Haffter,P. et al. The identification of genes with unique and essential functions in the development of the zebrafish, Danio rerio. Development 123, 1–36 ( 1996).
Ransom,D. G. et al. Characterization of zebrafish mutants with defects in embryonic hematopoiesis. Development 123, 311– 319 (1996).
Ransom,D. G. & Zon,L. I. in The Zebrafish: Genetics and Genomics (eds Detrich, H. W. I., Westerfield, M. & Zon, L. I.) 195 –210 (Academic, San Diego, 1999).
Vos,P. et al. AFLP: a new technique for DNA fingerprinting. Nucleic Acids Res. 23, 4407–4414 (1995).
Postlethwait,J. H. et al. Vertebrate genome evolution and the zebrafish gene map. Nature Genet. 18, 345–349 (1998).
Eisenstein,R. S. & Blemings,K. P. Iron regulatory proteins, iron responsive elements and iron homeostasis. J. Nutr. 128, 2295–2298 ( 1998).
Kimmel,C. B., Ballard,W. W., Kimmel,S. R., Ullmann,B. & Schilling,T. F. Stages of embryonic development of the zebrafish. Dev. Dyn. 203, 253– 310 (1995).
Richards,M. P. Trace mineral metabolism in the avian embryo. Poult. Sci. 76, 152–164 (1997).
Dumont,J. N. Oogenesis in Xenopus laevis (Daudin). VI. The route of injected tracer transport in the follicle and developing oocyte. J. Exp. Zool. 204, 193–217 ( 1978).
Craik,J. C. Levels of calcium and iron in the ovaries and eggs of cod Gadus morhua L. and plaice Pleuronectes platessa L. Comp. Biochem. Physiol. A. 83, 515–517 (1986).
Al-Adhami,M. A. & Kunz,Y. W. Ontogenesis of haematopoietic sites in brachydanio rerio (Hamilton–Buchanan) (Teleostei). Develop. Growth Differ. 19, 171–179 (1977).
Rieb,J.-P. La circulation sangunie chez l'embryon de Brachydanio rerio. Annales d'Embryologie et de Morphogenese 6, 43– 54 (1973).
Bannerman,R. M. Genetic defects of iron transport. Fed. Proc. 35, 2281–2285 (1976).
Kingston,P. J., Bannerman,C. E. & Bannerman, R. M. Iron deficiency anaemia in newborn sla mice: a genetic defect of placental iron transport. Br. J. Haematol. 40, 265–276 ( 1978).
Vulpe,C. D. et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nature Genet. 21, 195–199 ( 1999).
Askwith,C. et al. The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake. Cell 76, 403–410 (1994).
Stearman,R., Yuan,D. S., Yamaguchi-Iwai, Y., Klausner,R. D. & Dancis,A. A permease–oxidase complex involved in high-affinity iron uptake in yeast. Science 271, 1552–1557 (1996).
Westerfield,M. The Zebrafish Book (Univ. Oregon Press, Eugene, 1993 ).
Thompson,M. A. et al. The cloche and spadetail genes differentially affect hematopoiesis and vasculogenesis. Dev. Biol. 197, 248–269 (1998).
Knapik,E. W. et al. A microsatellite genetic linkage map for zebrafish. Nature Genet. 18, 338–343 (1998).
Johnson,S. L., Africa,D., Horne,S. & Postlethwait,J. H. Half-tetrad analysis in zebrafish: mapping the ros mutation and the centromere of linkage group I. Genetics 139, 1727– 1735 (1995).
Shimoda,N. et al. Zebrafish genetic map with 2000 microsatellite markers. Genomics 58, 219-232 (1999).
Farr,C. J., Saiki,R. K., Erlich,H. A., McCormick,F. & Marshall,C. J. Analysis of RAS gene mutations in acute myeloid leukemia by polymerase chain reaction and oligonucleotide probes. Proc. Natl Acad. Sci. USA 85, 1629 –1633 (1988).
Wood,W. I., Gitschier,J., Lasky,L. A. & Lawn,R. M. Base composition-independent hybridization in tetramethylammonium chloride: a method for oligonucleotide screening of highly complex gene libraries. Proc. Natl Acad. Sci. USA 82, 1585– 1588 (1985).
Palis,J. & Kingsley,P. D. Differential gene expression during early murine yolk sac development. Mol. Reprod. Dev. 42, 19–27 (1995).
Brownlie,A. et al. Positional cloning of the zebrafish sauternes gene: a model for congenital sideroblastic anaemia. Nature Genet. 20, 244–250 (1998).
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.
About this article
Frontiers in Physiology (2019)
New Insights into the Hepcidin-Ferroportin Axis and Iron Homeostasis in iPSC-Derived Cardiomyocytes from Friedreich’s Ataxia Patient
Oxidative Medicine and Cellular Longevity (2019)
Regulating ferroportin-1 and transferrin receptor-1 expression: A novel function of hydrogen sulfide
Journal of Cellular Physiology (2019)
Heart Failure Reviews (2019)