Dysregulation of ferroportin 1 interferes with spleen organogenesis in polycythaemia mice.
Regulatory interferences at the iron transporter ferroportin 1 (Fpn1) cause transient defects in iron homeostasis and erythropoiesis in polycythaemia (Pcm) mutant mice. The present study identified decreased Fpn1 expression in placental syncytiotrophoblast cells at late gestation as the mechanism of neonatal iron deficiency in Pcm mutants. Tissue specificity of embryonic Fpn1 dysregulation was evident from concomitant decreases in Fpn1 mRNA and protein expression in placenta and liver, as opposed to upregulation of Fpn1 protein despite decreased transcript levels in spleen, implicating post-transcriptional regulation of Fpn1. Dysregulation of Fpn1 and decreased iron levels in Pcm mutant spleens correlated with apoptotic cell death in the stroma, resulting in a semidominant spleen regression. At 7 weeks of age, a transient increase in spleen size in Pcm heterozygotes reflected a transient erythropoietin-mediated polycythemia. Structurally, Pcm mutant spleens displayed a severe defect in red pulp formation, including disruption of the sinusoidal endothelium, as well as discrete defects in white pulp organization during postnatal development. Reduced functional competence of the Pcm mutant spleen was manifested by an impaired response to chemically induced hemolytic anemia. Thus, aberrant Fpn1 regulation and iron homeostasis interferes with development of the spleen stroma during embryogenesis, resulting in a novel defect in spleen architecture postnatally.
Mok
Henry
H
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Mendoza
Miriam
M
Prchal
Josef T
JT
Balogh
Péter
P
Schumacher
Armin
A
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001483:Base Sequence; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis; D006579:Heterozygote; D006706:Homeostasis; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008805:Mice, Inbred A; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D008954:Models, Biological; D010920:Placenta / Q000378:metabolism; D011086:Polycythemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011247:Pregnancy; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000002:abnormalities / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism*; D000098742:Ferroportin
D027682:Cation Transport Proteins; D012333:RNA, Messenger; D000098742:Ferroportin; D007501:Iron