Transferrin Receptor Is Necessary for Proper Oligodendrocyte Iron Homeostasis and Development

To test the hypothesis that the transferrin (Tf) cycle has unique importance for oligodendrocyte development and function, we disrupted the expression of the Tf receptor (Tfr) gene in oligodendrocyte progenitor cells (OPCs) on mice of either sex using the Cre/lox system. This ablation results in the elimination of iron incorporation via the Tf cycle but leaves other Tf functions intact. Mice lacking Tfr, specifically in NG2 or Sox10-positive OPCs, developed a hypomyelination phenotype. Both OPC differentiation and myelination were affected, and Tfr deletion resulted in impaired OPC iron absorption. Specifically, the brains of Tfr cKO animals presented a reduction in the quantity of myelinated axons, as well as fewer mature oligodendrocytes. In contrast, the ablation of Tfr in adult mice affected neither mature oligodendrocytes nor myelin synthesis. RNA-seq analysis performed in Tfr cKO OPCs revealed misregulated genes involved in OPC maturation, myelination, and mitochondrial activity. Tfr deletion in cortical OPCs also disrupted the activity of the mTORC1 signaling pathway, epigenetic mechanisms critical for gene transcription and the expression of structural mitochondrial genes. RNA-seq studies were additionally conducted in OPCs in which iron storage was disrupted by deleting the ferritin heavy chain. These OPCs display abnormal regulation of genes associated with iron transport, antioxidant activity, and mitochondrial activity. Thus, our results indicate that the Tf cycle is central for iron homeostasis in OPCs during postnatal development and suggest that both iron uptake via Tfr and iron storage in ferritin are critical for energy production, mitochondrial activity, and maturation of postnatal OPCs.SIGNIFICANCE STATEMENT By knocking-out transferrin receptor (Tfr) specifically in oligodendrocyte progenitor cells (OPCs), we have established that iron incorporation via the Tf cycle is key for OPC iron homeostasis and for the normal function of these cells during the postnatal development of the CNS. Moreover, RNA-seq analysis indicated that both Tfr iron uptake and ferritin iron storage are critical for proper OPC mitochondrial activity, energy production, and maturation.