title: Severe iron deficiency anemia in transgenic mice expressing liver hepcidin.
abstract: We recently reported the hemochromatosis-like phenotype observed in our Usf2 knockout mice. In these mice, as in murine models of hemochromatosis and patients with hereditary hemochromatosis, iron accumulates in parenchymal cells (in particular, liver and pancreas), whereas the reticuloendothelial system is spared from this iron loading. We suggested that this phenotypic trait could be attributed to the absence, in the Usf2 knockout mice, of a secreted liver-specific peptide, hepcidin. We conjectured that the reverse situation, namely overexpression of hepcidin, might result in phenotypic traits of iron deficiency. This question was addressed by generating transgenic mice expressing hepcidin under the control of the liver-specific transthyretin promoter. We found that the majority of the transgenic mice were born with a pale skin and died within a few hours after birth. These transgenic animals had decreased body iron levels and presented severe microcytic hypochromic anemia. So far, three mosaic transgenic animals have survived. They were unequivocally identified by physical features, including reduced body size, pallor, hairless and crumpled skin. These pleiotropic effects were found to be associated with erythrocyte abnormalities, with marked anisocytosis, poikylocytosis and hypochromia, which are features characteristic of iron-deficiency anemia. These results strongly support the proposed role of hepcidin as a putative iron-regulatory hormone. The animal models devoid of hepcidin (the Usf2 knockout mice) or overexpressing the peptide (the transgenic mice presented in this paper) represent valuable tools for investigating iron homeostasis in vivo and for deciphering the molecular mechanisms of hepcidin action.
authors.affiliation: Département de génétique, développement et Pathologie Moléculaire, Institut Cochin, Centre National de la Recherche Scientifique, et Université René Descartes, Faculté de Médecine Cochin-Port Royal, 75014 Paris, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Nicolas
authors.forename: Myriam
authors.initials: M
authors.lastname: Bennoun
authors.forename: Arlette
authors.initials: A
authors.lastname: Porteu
authors.forename: Sandrine
authors.initials: S
authors.lastname: Mativet
authors.forename: Carole
authors.initials: C
authors.lastname: Beaumont
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
authors.forename: Mario
authors.initials: M
authors.lastname: Sirito
authors.forename: Michèle
authors.initials: M
authors.lastname: Sawadogo
authors.forename: Axel
authors.initials: A
authors.lastname: Kahn
authors.forename: Sophie
authors.initials: S
authors.lastname: Vaulont
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000209:etiology*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000502:physiology*; D001692:Biological Transport; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D064451:Hepcidins; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011228:Prealbumin / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D019076:Transgenes; D051720:Upstream Stimulatory Factors
chemical_list: D023181:Antimicrobial Cationic Peptides; D004268:DNA-Binding Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D011228:Prealbumin; D014157:Transcription Factors; D051720:Upstream Stimulatory Factors; C497186:Usf2 protein, mouse; D007501:Iron