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1.
Blood ; 113(12): 2843-50, 2009 Mar 19.
Article in English | MEDLINE | ID: mdl-19047682

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.


Subject(s)
Antimicrobial Cationic Peptides/biosynthesis , Gene Expression Regulation, Developmental/physiology , Hepcidins/physiology , Iron/metabolism , Transferrin/physiology , Zebrafish Proteins/physiology , 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
2.
Development ; 123: 311-9, 1996 Dec.
Article in English | MEDLINE | ID: mdl-9007251

ABSTRACT

As part of a large scale chemical mutagenesis screen of the zebrafish (Danio rerio) genome, we have identified 33 mutants with defects in hematopoiesis. Complementation analysis placed 32 of these mutants into 17 complementation groups. The allelism of the remaining 1 blood mutant is currently unresolved. We have categorized these blood mutants into four phenotypic classes based on analyses of whole embryos and isolated blood cells, as well as by in situ hybridization using the hematopoietic transcription factors GATA-1 and GATA-2. Embryos mutant for the gene moonshine have few if any proerythroblasts visible on the day circulation begins and normal erythroid cell differentiation is blocked as determined by staining for hemoglobin and GATA-1 expression. Mutations in five genes, chablis, frascati, merlot, retsina, thunderbird and two possibly unique mutations cause a progressive decrease in the number of blood cells during the first 5 days of development. Mutations in another seven genes, chardonnay, chianti, grenache, sauternes, weiflherbst and zinfandel, and two additional mutations result in hypochromic blood cells which also decrease in number as development proceeds. Several of these mutants have immature cells in the circulation, indicating a block in normal erythroid development. The mutation in zinfandel is dominant, and 2-day old heterozygous carriers fail to express detectable levels of hemoglobin and have decreasing numbers of circulating cells during the first 5 days of development. Mutations in two genes, freixenet and yquem, result in the animals that are photosensitive with autofluorescent blood, similar to that found in the human congenital porphyrias. The collection of mutants presented here represent several steps required for normal erythropoiesis. The analysis of these mutants provides a powerful approach towards defining the molecular mechanisms involved in vertebrate hematopoietic development.


Subject(s)
Hematopoiesis/genetics , Mutation , Zebrafish/embryology , Zebrafish/genetics , Anemia, Hypochromic/blood , Anemia, Hypochromic/embryology , Anemia, Hypochromic/genetics , Animals , Embryo, Nonmammalian/blood supply , Erythrocyte Count , Hemoglobins/metabolism , Light/adverse effects , Phenotype , Zebrafish/blood
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