Comparison of 3 Tfr2-deficient murine models suggests distinct functions for Tfr2-α and Tfr2-β isoforms in different tissues

Antonella Roetto, Ferdinando Di Cunto, Rosa Maria Pellegrino, Emilio Hirsch, Ornella Azzolino, Alessandro Bondi, Ilaria Defilippi, Sonia Carturan, Barbara Miniscalco, Fulvio Riondato, Daniela Cilloni, Lorenzo Silengo, Fiorella Altruda, Clara Camaschella, Giuseppe Saglio

Research output: Contribution to journalArticlepeer-review

Abstract

Transferrin receptor 2 (TFR2) is a transmembrane protein that is mutated in hemochromatosis type 3. The TFR2 gene is transcribed in 2 main isoforms: the full-length (α) and a shorter form (β). α-Tfr2 is the sensor of diferric transferrin, implicated in the modulation of hepcidin, the main regulator of iron homeostasis. The function of the putative β-Tfr2 protein is unknown. We have developed a new mouse model (KI) lacking β-Tfr2 compared with Tfr2 knockout mice (KO). Adult Tfr2 KO mice show liver iron overload and inadequate hepcidin levels relative to body iron stores, even though they increase Bmp6 production. KI mice have normal transferrin saturation, liver iron concentration, hepcidin and Bmp6 levels but show a transient anemia at young age and severe spleen iron accumulation in adult animals. Fpn1 is strikingly decreased in the spleen of these animals. These findings and the expression of β-Tfr2 in wild-type mice spleen suggest a role for β-Tfr2 in Fpn1 transcriptional control. Selective inactivation of liver α-Tfr2 in KI mice (LCKO-KI) returned the phenotype to liver iron overload. Our results strengthen the function of hepatic α-Tfr2 in hepcidin activation, suggest a role for extrahepatic Tfr2 and indicate that β-Tfr2 may specifically control spleen iron efflux.

Original languageEnglish
Pages (from-to)3382-3389
Number of pages8
JournalBlood
Volume115
Issue number16
DOIs
Publication statusPublished - Apr 22 2010

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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