Ferroportin1 is required for normal iron cycling in zebrafish.
Missense mutations in ferroportin1 (fpn1), an intestinal and macrophage iron exporter, have been identified between transmembrane helices 3 and 4 in the zebrafish anemia mutant weissherbst (weh(Tp85c-/-)) and in patients with type 4 hemochromatosis. To explore the effects of fpn1 mutation on blood development and iron homeostasis in the adult zebrafish, weh(Tp85c-/-) zebrafish were rescued by injection with iron dextran and studied in comparison with injected and uninjected WT zebrafish and heterozygotes. Although iron deposition was observed in all iron-injected fish, only weh(Tp85c-/-) zebrafish exhibited iron accumulation in the intestinal epithelium compatible with a block in iron export. Iron injections initially reversed the anemia. However, 8 months after iron injections were discontinued, weh(Tp85c-/-) zebrafish developed hypochromic anemia and impaired erythroid maturation despite the persistence of iron-loaded macrophages and elevated hepatic nonheme iron stores. Quantitative real-time RT-PCR revealed a significant decrease in mean hepatic transcript levels of the secreted iron-regulator hepcidin and increased intestinal expression of fpn1 in anemic weh(Tp85c-/-) adults. Injection of iron dextran into WT or mutant zebrafish embryos, however, resulted in significant increases in hepcidin expression 18 hours after injection, demonstrating that hepcidin expression in zebrafish is iron responsive and independent of fpn1's function as an iron exporter.
Fraenkel
Paula G
PG
Division of Hematology/Oncology, Children's Hospital, Karp Research Laboratories, Boston, Massachusetts 02115, USA.
Traver
David
D
Donovan
Adriana
A
Zahrieh
David
D
Zon
Leonard I
LI
D000747:Anemia, Hypochromic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D064451:Hepcidins; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000473:pathology; D017136:Ion Transport / Q000235:genetics; D007501:Iron / Q000008:administration & dosage / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D000098742:Ferroportin
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; D064451:Hepcidins; D029961:Zebrafish Proteins; D000098742:Ferroportin; D007501:Iron