Brain and retinal ferroportin 1 dysregulation in polycythaemia mice.
Disruption of iron homeostasis within the central nervous system (CNS) can lead to profound abnormalities during both development and aging in mammals. The radiation-induced polycythaemia (Pcm) mutation, a 58-bp microdeletion in the promoter region of ferroportin 1 (Fpn1), disrupts transcriptional and post-transcriptional regulation of this pivotal iron transporter. This regulatory mutation induces dynamic alterations in peripheral iron homeostasis such that newborn homozygous Pcm mice exhibit iron deficiency anemia with increased duodenal Fpn1 expression while adult homozygotes display decreased Fpn1 expression and anemia despite organismal iron overload. Herein we report the impact of the Pcm microdeletion on iron homeostasis in two compartments of the central nervous system: brain and retina. At birth, Pcm homozygotes show a marked decrease in brain iron content and reduced levels of Fpn1 expression. Upregulation of transferrin receptor 1 (TfR1) in brain microvasculature appears to mediate the compensatory iron uptake during postnatal development and iron content in Pcm brain is restored to wild-type levels by 7 weeks of age. Similarly, changes in expression are transient and expression of Fpn1 and TfR1 is indistinguishable between Pcm homozygotes and wild-type by 12 weeks of age. Strikingly, the adult Pcm brain is effectively protected from the peripheral iron overload and maintains normal iron content. In contrast to Fpn1 downregulation in perinatal brain, the retina of Pcm homozygotes reveals increased levels of Fpn1 expression. While retinal morphology appears normal at birth and during early postnatal development, adult Pcm mice demonstrate a marked, age-dependent loss of photoreceptors. This phenotype demonstrates the importance of iron homeostasis in retinal health.
Iacovelli
Jared
J
F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, 305 Stellar-Chance Labs, 422 Curie Blvd, Philadelphia, PA 19104, USA.
Mlodnicka
Agnieska E
AE
Veldman
Peter
P
Ying
Gui-Shuang
GS
Dunaief
Joshua L
JL
Schumacher
Armin
A
D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002452:Cell Count; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D006706:Homeostasis; D006720:Homozygote; D007150:Immunohistochemistry; D007501:Iron / Q000032:analysis; D000090463:Iron Deficiencies; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism; D011086:Polycythemia / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D000098742:Ferroportin
D027682:Cation Transport Proteins; D012333:RNA, Messenger; D000098742:Ferroportin; D007501:Iron