title: Comparison of 3 Tfr2-deficient murine models suggests distinct functions for Tfr2-alpha and Tfr2-beta isoforms in different tissues.
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 (alpha) and a shorter form (beta). alpha-Tfr2 is the sensor of diferric transferrin, implicated in the modulation of hepcidin, the main regulator of iron homeostasis. The function of the putative beta-Tfr2 protein is unknown. We have developed a new mouse model (KI) lacking beta-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 beta-Tfr2 in wild-type mice spleen suggest a role for beta-Tfr2 in Fpn1 transcriptional control. Selective inactivation of liver alpha-Tfr2 in KI mice (LCKO-KI) returned the phenotype to liver iron overload. Our results strengthen the function of hepatic alpha-Tfr2 in hepcidin activation, suggest a role for extrahepatic Tfr2 and indicate that beta-Tfr2 may specifically control spleen iron efflux.
authors.affiliation: Department of Clinical and Biological Science, University of Torino, Turin, Italy. antonella.roetto@unito.it
authors.forename: Antonella
authors.initials: A
authors.lastname: Roetto
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Di Cunto
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Pellegrino
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Ornella
authors.initials: O
authors.lastname: Azzolino
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bondi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Defilippi
authors.forename: Sonia
authors.initials: S
authors.lastname: Carturan
authors.forename: Barbara
authors.initials: B
authors.lastname: Miniscalco
authors.forename: Fulvio
authors.initials: F
authors.lastname: Riondato
authors.forename: Daniela
authors.initials: D
authors.lastname: Cilloni
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Silengo
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.forename: Clara
authors.initials: C
authors.lastname: Camaschella
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D015153:Blotting, Western; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism; D064451:Hepcidins; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; C579599:Hamp protein, mouse; D064451:Hepcidins; D020033:Protein Isoforms; D011990:Receptors, Transferrin; D007501:Iron