A critical role for murine transferrin receptor 2 in erythropoiesis during iron restriction

Wallace, D.F., Secondes, E.S., Rishi, G.A., Ostini, L., Mcdonald, C.J., Lane, S.W., Vui, T., Hooper, J.D., Velasco, G., Ramsay, A.J., Lopez Otin, C., & Subramaniam, V.N. (2015) A critical role for murine transferrin receptor 2 in erythropoiesis during iron restriction. British Journal of Haematology, 168(6), pp. 891-901.

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Effective erythropoiesis requires an appropriate supply of iron and mechanisms regulating iron homeostasis and erythropoiesis are intrinsically linked. Iron dysregulation, typified by iron-deficiency anaemia and iron overload, is common in many clinical conditions and impacts the health of up to 30 of the world's population. The proteins transmembrane protease, serine 6 (TMPRSS6; also termed matriptase-2), HFE and transferrin receptor 2 (TFR2) play important and opposing roles in systemic iron homeostasis, by regulating expression of the iron regulatory hormone hepcidin. We have performed a systematic analysis of mice deficient in these three proteins and show that TMPRSS6 predominates over HFE and TFR2 in hepcidin regulation. The phenotype of mice lacking TMPRSS6 and TFR2 is characterized by severe anaemia and extramedullary haematopoiesis in the spleen. Stress erythropoiesis in these mice results in increased expression of the newly identified erythroid iron regulator erythroferrone, which does not appear to overcome the hepcidin overproduction mediated by loss of TMPRSS6. Extended analysis reveals that TFR2 plays an important role in erythroid cells, where it is involved in terminal erythroblast differentiation and the regulation of erythropoietin. In conclusion, we have identified an essential role for TFR2 in erythropoiesis that may provide new targets for the treatment of anaemia.

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ID Code: 99756
Item Type: Journal Article
Refereed: Yes
Keywords: erythroferrone; erythropoietin; hepcidin; HFE protein; matriptase; matriptase 2; regulator protein; transferrin receptor 2; unclassified drug; erythropoietin; erythropoietin receptor; hepcidin; Hfe protein, mouse; HLA antigen class 1; matriptase 2; membrane protein; serine proteinase; transferrin receptor; Trfr2 protein, Receptors, animal cell; animal tissue; Article; cell differentiation; cell surface; controlled study; disease severity; erythroblast; erythroid cell; erythroid precursor cell; erythropoiesis; extramedullary hematopoiesis; flow cytometry; hormone synthesis; iron defi, Anemia, Iron-Deficiency; Animals; Cell Differentiation; Erythroid Cells; Erythropoiesis; Erythropoietin; Hematopoiesis, Extramedullary; Hepcidins; Histocompatibility Antigens Class I; Kidney; Liver; Male; Membrane Proteins; Mice; Mice, Knockout;, Erythropoietin;, Transferrin; Serine Endopeptidases; Splenomegaly
DOI: 10.1111/bjh.13225
ISSN: 1365-2141
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Copyright Owner: Copyright © 2014 John Wiley & Sons Ltd
Deposited On: 12 Oct 2016 05:40
Last Modified: 14 Oct 2016 04:33

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