Thechiantizebrafish mutant provides a model for erythroid-specific disruption oftransferrin receptor 1
Author:
Wingert Rebecca A.1, Brownlie Alison1, Galloway Jenna L.1, Dooley Kimberly1, Fraenkel Paula1, Axe Jennifer L.1, Davidson Alan J.1, Barut Bruce1, Noriega Laura1, Sheng Xiaoming1, Zhou Yi1, Zon Leonard I.1
Affiliation:
1. Department of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
Abstract
Iron is a crucial metal for normal development, being required for the production of heme, which is incorporated into cytochromes and hemoglobin. The zebrafish chianti (cia) mutant manifests a hypochromic,microcytic anemia after the onset of embryonic circulation, indicative of a perturbation in red blood cell hemoglobin production. We show that cia encodes tfr1a, which is specifically expressed in the developing blood and requisite only for iron uptake in erythroid precursors. In the process of isolating zebrafish tfr1, we discovered two tfr1-like genes (tfr1a and tfr1b) and a single tfr2 ortholog. Abrogation of tfr1b function using antisense morpholinos revealed that this paralog was dispensable for hemoglobin production in red cells. tfr1b morphants exhibited growth retardation and brain necrosis, similar to the central nervous system defects observed in the Tfr1 null mouse, indicating that tfr1b is probably used by non-erythroid tissues for iron acquisition. Overexpression of mouse Tfr1, mouse Tfr2, and zebrafish tfr1b partially rescued hypochromia in cia embryos, establishing that each of these transferrin receptors are capable of supporting iron uptake for hemoglobin production in vivo. Taken together, these data show that zebrafish tfr1a and tfr1b share biochemical function but have restricted domains of tissue expression, and establish a genetic model to study the specific function of Tfr1 in erythroid cells.
Publisher
The Company of Biologists
Subject
Developmental Biology,Molecular Biology
Reference69 articles.
1. Aisen, P. (2004). Molecules in focus:Transferrin receptor 1. Int. J. Biochem. Cell Biol.36,2137-2143. 2. Amores, A., Force, A., Yan, Y. L., Joly, L., Amemiya, C., Fritz,A., Ho, R. H., Langeland, J., Prince, V., Wang, Y. L. et al.(1998). Zebrafish hox clusters and vertebrate genome evolution. Science282,1711-1714. 3. Andrews, N. C. (1999). Disorders of iron metabolism. N. Engl. J. Med.341,1986-1995. 4. Andrews, N. C. (2000). Iron homeostasis:insights from genetics and animal models. Nat. Rev. Genet.1,208-217. 5. Aparicio, S., Hawker, K., Cottage, A., Mikawa, Y., Zuo, L.,Venkatesh, B., Chen, E., Krumlauf, R. and Brenner, S.(1997). Organization of the Fugu rubripes Hox clusters: evidence for continuing evolution of vertebrate Hox complexes. Nat. Genet.16,79-83.
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