title: Abnormal body iron distribution and erythropoiesis in a novel mouse model with inducible gain of iron regulatory protein (IRP)-1 function.
abstract: Disorders of iron metabolism account for some of the most common human diseases. Cellular iron homeostasis is maintained by iron regulatory proteins (IRP)-1 and 2 through their binding to cis-regulatory iron-responsive elements (IREs) in target mRNAs. Mouse models with IRP deficiency have yielded valuable insights into iron biology, but the physiological consequences of gain of IRP function in mammalian organisms have remained unexplored. Here, we report the generation of a mouse line allowing conditional expression of a constitutively active IRP1 mutant (IRP1) using Cre/Lox technology. Systemic activation of the IRP1 transgene from the Rosa26 locus yields viable animals with gain of IRE-binding activity in all the organs analyzed. IRP1 activation alters the expression of IRP target genes and is accompanied by iron loading in the same organs. Furthermore, mice display macrocytic erythropenia with decreased hematocrit and hemoglobin levels as well as impaired erythroid differentiation. Thus, inappropriately high IRP1 activity causes disturbed body iron distribution and erythropoiesis. This new mouse model further highlights the importance of appropriate IRP regulation in central organs of iron metabolism. Moreover, it opens novel avenues to study diseases associated with abnormally high IRP1 activity, such as Parkinson's disease or Friedreich's ataxia.
authors: European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: D
authors: D
authors: Casarrubea
authors: L
authors: L
authors: Viatte
authors: T
authors: T
authors: Hallas
authors: A
authors: A
authors: Vasanthakumar
authors: R S
authors: RS
authors: Eisenstein
authors: K
authors: K
authors: Schümann
authors: M W
authors: MW
authors: Hentze
authors: B
authors: B
authors: Galy
mesh_terms: D000748:Anemia, Macrocytic / Q000378:metabolism; D000818:Animals; D004386:Duodenum / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology; D005260:Female; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000235:genetics* / Q000378:metabolism*; D035925:Iron-Regulatory Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013154:Spleen / Q000378:metabolism
chemical_list: D035925:Iron-Regulatory Proteins; D007501:Iron; D035941:Iron Regulatory Protein 1