Transferrin-a modulates hepcidin expression in zebrafish embryos.
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.
Fraenkel
Paula G
PG
Division of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. pfraenke@bidmc.harvard.edu
Gibert
Yann
Y
Holzheimer
Jason L
JL
Lattanzi
Victoria J
VJ
Burnett
Sarah F
SF
Dooley
Kimberly A
KA
Wingert
Rebecca A
RA
Zon
Leonard I
LI
D000595:Amino Acid Sequence; D000747:Anemia, Hypochromic / Q000139:chemically induced / Q000196:embryology / Q000235:genetics; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D055785:Gene Knockdown Techniques; D064451:Hepcidins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D009154:Mutation; D009928:Organ Specificity; D010659:Phenylhydrazines / Q000633:toxicity; D011990:Receptors, Transferrin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D014168:Transferrin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000099236:Solute Carrier Family 11, Member 2
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D064451:Hepcidins; D007501:Iron; D010659:Phenylhydrazines; D011990:Receptors, Transferrin; D014168:Transferrin; D029961:Zebrafish Proteins; D000099236:Solute Carrier Family 11, Member 2; C578702:HAMP protein, human; C000618866:hamp protein, zebrafish; C540058:tfa protein, zebrafish; C503642:tfr2 protein, zebrafish; C030299:phenylhydrazine