Submitted June 30, 2008
Accepted November 13, 2008
Transferrin-a modulates hepcidin expression in zebrafish embryos
Paula G. Fraenkel*, Yann Gibert, Jason L Holzheimer, Victoria J Lattanzi, Sarah F Burnett, Kimberly A Dooley, Rebecca A Wingert, and Leonard I Zon
Division of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
Broad Institute, Massachusetts Institute of Technology, Cambridge, MA, United States
Massachusetts General Hospital, Boston, MA, United States
Division of Hematology/Oncology and Howard Hughes Medical Institute, Children's Hospital, Boston, MA, United States
* Corresponding author; email: pfraenke{at}bidmc.harvard.edu.
The iron regulatory hormone hepcidin is transcriptionally upregulated 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 co-injection 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.
