Abstract
The Transferrin Receptor 2 (Tfr2) modulates systemic iron metabolism through the regulation of iron regulator Hepcidin (Hepc) and Tfr2 inactivation causes systemic iron overload. Based on data demonstrating Tfr2 expression in brain, we analysed Tfr2-KO mice in order to examine the molecular, histological and behavioural consequences of Tfr2 silencing in this tissue. Tfr2 abrogation caused an accumulation of iron in specific districts in the nervous tissue that was not accompanied by a brain Hepc response. Moreover, Tfr2-KO mice presented a selective overactivation of neurons in the limbic circuit and the emergence of an anxious-like behaviour. Furthermore, microglial cells showed a particular sensitivity to iron perturbation. We conclude that Tfr2 is a key regulator of brain iron homeostasis and propose a role for Tfr2 alpha in the regulation of anxiety circuits.
Highlights
It is generally accepted that iron enters neurons[10], microglial[17,18] and choroid plexi cells[19] bound to Tfr[1] and it has been shown that the iron hormone Hepc is expressed in the brain[20,21,22,23], similar to other Hepc regulatory proteins[10]
Tfr[2] alpha protein in total brain extracts showed a trend to decrease in wild type (WT) iron deficient diet (IDD) mice compared to WT mice, while it did not vary in WT iron enriched diet (IED) animals (Fig. 1B)
These data are in line with the role of Tfr[2] as an iron sensor contributing to iron homeostasis and with previous data demonstrating that Tfr[2] protein is stabilized on plasma membranes by iron loaded Transferrin (Fe-Tf)[37]
Summary
It is generally accepted that iron enters neurons[10], microglial[17,18] and choroid plexi cells[19] bound to Tfr[1] and it has been shown that the iron hormone Hepc is expressed in the brain[20,21,22,23], similar to other Hepc regulatory proteins[10]. It is still unclear how iron levels and localization are regulated in cerebral compartments. To distinguish the effects of Tfr[2] abrogation from those due to Tfr2-independent iron load modifications, we examined WT sib pairs subjected to an iron enriched diet (IED) and WT or Tfr2-KO mice upon an iron deficient diet (IDD)
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