H-ferritin expression in astrocytes is necessary for proper oligodendrocyte development and myelination.

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 1 (Tfr1), and the ferritin heavy subunit (Fth) in Glast-1-positive astrocytes. DMT1 or Tfr1 ablation in astrocytes throughout early brain development did not significantly affects oligodendrocyte maturation or iron homeostasis. However, blocking Fth production in astrocytes during the first postnatal week drastically delayed oligodendrocyte development and myelin synthesis. Fth knockout animals presented an important decrease in the number of myelinating oligodendrocytes and a substantial reduction in the percentage of myelinated axons. This postnatal hypomyelination was accompanied by a decline in oligodendrocyte iron uptake and with an increase in brain oxidative stress. We also tested the relevance of astrocytic Fth expression in the cuprizone model of myelin damage and repair. Fth deletion in Glast1-positive astrocytes significantly reduced myelin production and the density of mature myelinating oligodendrocytes throughout the complete remyelination process. These results indicate that Fth iron storage in astrocytes is vital for early oligodendrocyte development as well as for the remyelination of the CNS.