How iron is delivered to the CNS for myelination is poorly understood. Astrocytes are the most abundant glial cells in the brain and are the only cells in close contact with blood vessels. Therefore, they are strategically located to obtain nutrients, such as iron, from circulating blood. To determine the importance of astrocyte iron uptake and storage in myelination and remyelination, we conditionally knocked-out the expression of the divalent metal transporter 1 (DMT1), the transferrin receptor

To define the importance of iron storage in oligodendrocyte development and function, the ferritin heavy subunit (Fth) was specifically deleted in oligodendroglial cells. Blocking Fth synthesis in Sox10 or NG2-positive oligodendrocytes during the first or the third postnatal week significantly reduces oligodendrocyte iron storage and maturation. The brain of Fth KO animals presented an important decrease in the expression of myelin proteins and a substantial reduction in the percentage of myelinated axons. This hypomyelination was accompanied by a decline in the number of myelinating oligodendrocytes and with a reduction in proliferating oligodendrocyte progenitor cells (OPCs). Importantly, deleting Fth in Sox10-positive oligodendroglial cells after postnatal day 60 has no effect on myelin production and/or oligodendrocyte quantities. We also tested the capacity of Fth-deficient OPCs to remyelinate the adult brain in the cuprizone model of myelin injury and repair. Fth deletion in NG2-positive OPCs significantly reduces the number of mature oligodendrocytes and myelin production throughout the remyelination process. Furthermore, the corpus callosum of Fth KO animals presented a significant decrease in the percentage of remyelinated axons and a substantial reduction in the average myelin thickness. These results indicate that Fth synthesis during the first three postnatal weeks is important for an appropriate oligodendrocyte development, and suggest that Fth iron storage in adult OPCs is also essential for an effective remyelination of the mouse brain.SIGNIFICANCE STATEMENTTo define the importance of iron storage in oligodendrocyte function, we have deleted the ferritin heavy chain (Fth) specifically in the oligodendrocyte lineage. Fth ablation in oligodendroglial cells throughout early postnatal development significantly reduces oligodendrocyte maturation and myelination. In contrast, deletion of Fth in oligodendroglial cells after postnatal day 60 has no effect on myelin production and/or oligodendrocyte numbers. We have also tested the consequences of disrupting Fth iron storage in oligodendrocyte progenitor cells (OPCs) after demyelination. We have found that Fth deletion in NG2-positive OPCs significantly delays the remyelination process in the adult brain. Therefore, Fth iron storage is essential for early oligodendrocyte development as well as for OPC maturation in the demyelinated adult brain.

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