The erythroid function of transferrin receptor 2 revealed by Tmprss6 inactivation in different models of transferrin receptor 2 knockout mice

Antonella Nai, Rosa M. Pellegrino, Marco Rausa, Alessia Pagani, Martina Boero, Laura Silvestri, Giuseppe Saglio, Antonella Roetto, Clara Camaschella

Research output: Contribution to journalArticlepeer-review

Abstract

Transferrin receptor 2 (TFR2) is a transmembrane glycoprotein expressed in the liver and in the erythroid compartment, mutated in a form of hereditary hemochromatosis. Hepatic TFR2, together with HFE, activates the transcription of the iron-regulator hepcidin, while erythroid TFR2 is a member of the erythropoietin receptor complex. The TMPRSS6 gene, encoding the liver-expressed serine protease matriptase-2, is the main inhibitor of hepcidin and inactivation of TMPRSS6 leads to iron deficiency with high hepcidin levels. Here we evaluate the phenotype resulting from the genetic loss of Tmprss6 in Tfr2 total (Tfr2-/-) and liver-specific (Tfr2LCKO) knockout mice. Tmprss6-/- Tfr2-/- and Tmprss6-/-Tfr2LCKO mice have increased hepcidin levels and show iron-deficiency anemia like Tmprss6-/- mice. However, while Tmprss6-/-Tfr2LCKO are phenotypically identical to Tmprss6-/- mice, Tmprss6-/-Tfr2-/- mice have increased red blood cell count and more severe microcytosis than Tmprss6-/- mice. In addition hepcidin expression in Tmprss6-/-Tfr2-/- mice is higher than in the wild-type animals, but lower than in Tmprss6-/- mice, suggesting partial inhibition of the hepcidin activating pathway. Our results prove that hepatic TFR2 acts upstream of TMPRSS6. In addition Tfr2 deletion causes a relative erythrocytosis in iron-deficient mice, which likely attenuates the effect of over-expression of hepcidin in Tmprss6-/- mice. Since liver-specific deletion of Tfr2 in Tmprss6-/- mice does not modify the erythrocyte count, we speculate that loss of Tfr2 in the erythroid compartment accounts for the hematologic phenotype of Tmprss6-/-Tfr2-/- mice. We propose that TFR2 is a limiting factor for erythropoiesis, particularly in conditions of iron restriction.

Original languageEnglish
Pages (from-to)1016-1021
Number of pages6
JournalHaematologica
Volume99
Issue number6
DOIs
Publication statusPublished - Jun 1 2014

ASJC Scopus subject areas

  • Hematology
  • Medicine(all)

Fingerprint Dive into the research topics of 'The erythroid function of transferrin receptor 2 revealed by Tmprss6 inactivation in different models of transferrin receptor 2 knockout mice'. Together they form a unique fingerprint.

Cite this