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.