Transferrin receptor is necessary for development of erythrocytes and the nervous system

Abstract

Plasma iron circulates bound to transferrin (Trf), which solubilizes the ferric ion and attenuates its reactivity. Diferric Trf interacts with cell-surface Trf receptor (Trfr) to undergo receptor-mediated endocytosis into specialized endosomes. Endosomal acidification leads to iron release, and iron is transported out of the endosome through the activity of divalent metal transporter 1 (DMT1, formerly Nramp2), a transmembrane iron transporter that functions only at low pH. Trf and Trfr then return to the cell surface for reuse, completing a highly efficient cycle. Although the Trf cycle is assumed to be the general mechanism for cellular iron uptake, this has not been validated experimentally. Mice with hypotransferrinaemia (hpx) have little or no plasma Trf. They have severe anaemia, indicating that the Trf cycle is essential for iron uptake by erythroid cells. Other hpx tissues, however, are generally normal, and there is a paradoxical increase in intestinal iron absorption and iron storage. To test the hypothesis that the Trf cycle has unique importance for erythropoiesis, we disrupted the Trfr gene in mice. This results in elimination of the Trf cycle, but leaves other Trf functions intact. Mice lacking Trfr have a more severe phenotype than hpx mice, affecting both erythropoiesis and neurologic development. Furthermore, haploinsufficiency for Trfr results in impaired erythroid development and abnormal iron homeostasis.

Erythrocytic Iron Deficiency Enhances Susceptibility to Plasmodium chabaudi Infection in Mice Carrying a Missense Mutation in Transferrin Receptor 1

“…Additionally, microcytosis was accompanied by an increased blood count, resulting in a normal overall hemoglobin level and hematocrit. Previously characterized mutant mouse lines displaying microcytosis and reduced surface levels of TFR1 on erythroblasts, including the heterozygous knockout mouse line Tfrc Ϫ/ϩ , exhibit a similar phenotype (24,44,45). Given that we also observed reduced TFR1 on the surfaces of mutant erythroblasts, our explanation for the microcytosis in the Tfrc MRI24910/ϩ line is a reduction of iron transport into cells during erythropoiesis.…”

“…The Tfrc gene, located at 32.6 Mbp, was selected as an ideal candidate. A deficiency in this gene has been reported to cause a similar dominant microcytosis phenotype (24). Sanger sequencing of all exons of the Tfrc gene revealed a T-to-C transition in exon 5 leading to a serine-to-proline substitution (S161P) (see Fig.…”

“…Mice with mutations induced in TFR1 to promote or prevent binding of HFE display decreased or increased hepcidin expression, respectively (26). The expression of TFR1 also affects erythrocyte physiology, with TFR1 deficiency resulting in reduced iron uptake by erythrocyte progenitors and microcytosis in a manner similar to that with dietary iron deficiency (24).…”

“…Transferrin receptor 1 (TFR1) is a major protein involved in transporting iron into cells via the iron carrier transferrin and is essential for erythropoiesis (24). It also regulates iron homeostasis through its interaction with the hemochromatosis protein (HFE), which in turn influences hepcidin expression (25)(26)(27).…”

Mitochondrial DNA-HVR1 Variation Reveals Genetic Heterogeneity in Thai-Isan Peoples from the Lower Region of Northeastern Thailand

“…Sequencing reactions were performed using a published set of primers (Kampuansai et al, 2007). The sequencing results were edited, assembled and aligned with the revised Cambridge Reference Sequence (Andrews et al, 1999) using SeqScape software v.2.0 (Applied Biosystem, Foster City, CA). The mtDNA …”