title: The second transferrin receptor regulates red blood cell production in mice.
abstract: Transferrin receptor 2 (TFR2) contributes to hepcidin regulation in the liver and associates with erythropoietin receptor in erythroid cells. Nevertheless, TFR2 mutations cause iron overload (hemochromatosis type 3) without overt erythroid abnormalities. To clarify TFR2 erythroid function, we generated a mouse lacking Tfr2 exclusively in the bone marrow (Tfr2(BMKO)). Tfr2(BMKO) mice have normal iron parameters, reduced hepcidin levels, higher hemoglobin and red blood cell counts, and lower mean corpuscular volume than normal control mice, a phenotype that becomes more evident in iron deficiency. In Tfr2(BMKO) mice, the proportion of nucleated erythroid cells in the bone marrow is higher and the apoptosis lower than in controls, irrespective of comparable erythropoietin levels. Induction of moderate iron deficiency increases erythroblasts number, reduces apoptosis, and enhances erythropoietin (Epo) levels in controls, but not in Tfr2(BMKO) mice. Epo-target genes such as Bcl-xL and Epor are highly expressed in the spleen and in isolated erythroblasts from Tfr2(BMKO) mice. Low hepcidin expression in Tfr2(BMKO) is accounted for by erythroid expansion and production of the erythroid regulator erythroferrone. We suggest that Tfr2 is a component of a novel iron-sensing mechanism that adjusts erythrocyte production according to iron availability, likely by modulating the erythroblast Epo sensitivity.
authors.affiliation: Vita Salute San Raffaele University, Milan, Italy; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy; and.
authors.forename: Antonella
authors.initials: A
authors.lastname: Nai
authors.affiliation: Vita Salute San Raffaele University, Milan, Italy; San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Gene Therapy and Stem Cells, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Lidonnici
authors.affiliation: Vita Salute San Raffaele University, Milan, Italy; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy; and.
authors.forename: Marco
authors.initials: M
authors.lastname: Rausa
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Gene Therapy and Stem Cells, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Mandelli
authors.affiliation: Vita Salute San Raffaele University, Milan, Italy; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy; and.
authors.forename: Alessia
authors.initials: A
authors.lastname: Pagani
authors.affiliation: Vita Salute San Raffaele University, Milan, Italy; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy; and.
authors.forename: Laura
authors.initials: L
authors.lastname: Silvestri
authors.affiliation: Vita Salute San Raffaele University, Milan, Italy; San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Gene Therapy and Stem Cells, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Ferrari
authors.affiliation: Vita Salute San Raffaele University, Milan, Italy; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy; and.
authors.forename: Clara
authors.initials: C
authors.lastname: Camaschella
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000502:physiology*; D004920:Erythropoiesis / Q000235:genetics*; D004921:Erythropoietin / Q000378:metabolism; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D064451:Hepcidins / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011990:Receptors, Transferrin / Q000502:physiology*
chemical_list: C579599:Hamp protein, mouse; D006454:Hemoglobins; D064451:Hepcidins; D011990:Receptors, Transferrin; C503641:TFR2 protein, mouse; D004921:Erythropoietin; D007501:Iron