title: Severe microcytic anemia but increased erythropoiesis in mice lacking Hfe or Tfr2 and Tmprss6.
abstract: Cell surface proteins Hfe, Tfr2, hemojuvelin and Tmprss6 play key roles in iron homeostasis. Hfe and Tfr2 induce transcription of hepcidin, a small peptide that promotes the degradation of the iron transporter ferroportin. Hemojuvelin, a co-receptor for bone morphogenic proteins, induces hepcidin transcription through a Smad signaling pathway. Tmprss6 (also known as matriptase-2), a membrane serine protease that has been found to bind and degrade hemojuvelin in vitro, is a potent suppressor of hepcidin expression. In order to examine if Hfe and Tfr2 are substrates for Tmprss6, we generated mice lacking functional Hfe or Tfr2 and Tmprss6. We found that double mutant mice lacking functional Hfe or Tfr2 and Tmprss6 exhibited a severe iron deficiency microcytic anemia phenotype mimicking the phenotype of single mutant mice lacking functional Tmprss6 (Tmprss6msk/msk mutant) demonstrating that Hfe and Tfr2 are not substrates for Tmprss6. Nevertheless, the phenotype of the mice lacking Hfe or Tfr2 and Tmprss6 differed from Tmprss6 deficient mice alone, in that the double mutant mice exhibited much greater erythropoiesis. Hfe and Tfr2 have been shown to play important roles in the erythron, independent of their role in regulating liver hepcidin transcription. We demonstrate that lack of functional Tfr2 and Hfe allows for increased erythropoiesis even in the presence of high hepcidin expression, but the high levels of hepcidin levels significantly limit the availability of iron to the erythron, resulting in ineffective erythropoiesis. Furthermore, repression of hepcidin expression by hypoxia was unaffected by the loss of functional Hfe, Tfr2 and Tmprss6.
authors.affiliation: The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, CA, USA. plee@scripps.edu
authors.forename: Pauline
authors.initials: P
authors.lastname: Lee
authors.forename: Mei-Hui
authors.initials: MH
authors.lastname: Hsu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Welser-Alves
authors.forename: Hongfan
authors.initials: H
authors.lastname: Peng
mesh_terms: D000747:Anemia, Hypochromic / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D004920:Erythropoiesis / Q000235:genetics*; D004921:Erythropoietin / Q000097:blood; D005260:Female; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D000860:Hypoxia / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011990:Receptors, Transferrin / Q000172:deficiency* / Q000235:genetics; D045262:Reticulocytosis / Q000235:genetics; D012697:Serine Endopeptidases / Q000172:deficiency* / Q000235:genetics
chemical_list: D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D004921:Erythropoietin; D012697:Serine Endopeptidases; C467801:matriptase 2