1. Transferrin-a modulates hepcidin expression in zebrafish embryos.
- Author
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Fraenkel PG, Gibert Y, Holzheimer JL, Lattanzi VJ, Burnett SF, Dooley KA, Wingert RA, and Zon LI
- Subjects
- Amino Acid Sequence, Anemia, Hypochromic chemically induced, Anemia, Hypochromic embryology, Anemia, Hypochromic genetics, Animals, Antimicrobial Cationic Peptides genetics, Cation Transport Proteins genetics, Embryo, Nonmammalian drug effects, Embryo, Nonmammalian metabolism, Erythropoiesis drug effects, Erythropoiesis genetics, Gene Expression Regulation, Developmental drug effects, Gene Knockdown Techniques, Hepcidins biosynthesis, Hepcidins deficiency, Hepcidins genetics, Humans, Iron pharmacology, Molecular Sequence Data, Mutation, Organ Specificity, Phenylhydrazines toxicity, Receptors, Transferrin antagonists & inhibitors, Receptors, Transferrin genetics, Receptors, Transferrin physiology, Sequence Alignment, Sequence Homology, Amino Acid, Species Specificity, Transferrin deficiency, Transferrin genetics, Zebrafish embryology, Zebrafish Proteins biosynthesis, Zebrafish Proteins deficiency, Zebrafish Proteins genetics, Antimicrobial Cationic Peptides biosynthesis, Gene Expression Regulation, Developmental physiology, Hepcidins physiology, Iron metabolism, Transferrin physiology, Zebrafish Proteins physiology
- Abstract
The iron regulatory hormone hepcidin is transcriptionally up-regulated in response to iron loading, but the mechanisms by which iron levels are sensed are not well understood. Large-scale genetic screens in the zebrafish have resulted in the identification of hypochromic anemia mutants with a range of mutations affecting conserved pathways in iron metabolism and heme synthesis. We hypothesized that transferrin plays a critical role both in iron transport and in regulating hepcidin expression in zebrafish embryos. Here we report the identification and characterization of the zebrafish hypochromic anemia mutant, gavi, which exhibits transferrin deficiency due to mutations in transferrin-a. Morpholino knockdown of transferrin-a in wild-type embryos reproduced the anemia phenotype and decreased somite and terminal gut iron staining, while coinjection of transferrin-a cRNA partially restored these defects. Embryos with transferrin-a or transferrin receptor 2 (TfR2) deficiency exhibited low levels of hepcidin expression, however anemia, in the absence of a defect in the transferrin pathway, failed to impair hepcidin expression. These data indicate that transferrin-a transports iron and that hepcidin expression is regulated by a transferrin-a-dependent pathway in the zebrafish embryo.
- Published
- 2009
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