Hunter James Kelly Research Institute, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, New York 14203.
Hunter James Kelly Research Institute, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, New York 14203
J Neurosci. 2020 Sep 30;40(40):7609-7624. doi: 10.1523/JNEUROSCI.1281-20.2020. Epub 2020 Aug 31.
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. To 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.
为了明确铁储存对少突胶质细胞发育和功能的重要性，我们特异性地在少突胶质细胞中敲除了铁蛋白重链（Fth）。在生后第一或第三周阻断 Sox10 或 NG2 阳性少突胶质细胞中的 Fth 合成，会显著减少少突胶质细胞的铁储存和成熟。Fth KO 动物的大脑中少突胶质细胞髓鞘蛋白的表达显著减少，髓鞘化轴突的比例也显著降低。这种少突胶质细胞脱髓鞘伴随着少突胶质细胞数量的减少和增殖性少突胶质前体细胞（OPC）的减少。重要的是，在生后 60 天后特异性敲除 Sox10 阳性少突胶质细胞中的 Fth 对髓鞘生成和/或少突胶质细胞数量没有影响。我们还在髓鞘损伤和修复的 Cuprizone 模型中测试了 Fth 缺陷的 OPC 再髓鞘化的能力。NG2 阳性 OPC 中的 Fth 缺失显著减少了整个再髓鞘化过程中成熟少突胶质细胞的数量和髓鞘的生成。此外，Fth KO 动物的胼胝体中再髓鞘化轴突的比例显著降低，平均髓鞘厚度也显著降低。这些结果表明，生后前 3 周内 Fth 的合成对于少突胶质细胞的正常发育非常重要，并表明 Fth 铁储存对成年 OPC 的有效再髓鞘化也是必不可少的。为了明确铁储存对少突胶质细胞功能的重要性，我们特异性地在少突胶质细胞谱系中敲除了铁蛋白重链（Fth）。在早期出生后发育过程中，敲除少突胶质细胞中的 Fth 会显著减少少突胶质细胞的成熟和髓鞘化。相比之下，生后 60 天后敲除少突胶质细胞中的 Fth 对髓鞘生成和/或少突胶质细胞数量没有影响。我们还测试了在脱髓鞘后破坏少突胶质细胞前体细胞（OPC）中的 Fth 铁储存的后果。我们发现，在 NG2 阳性 OPC 中敲除 Fth 会显著延迟成年大脑中的再髓鞘化过程。因此，Fth 铁储存对于早期少突胶质细胞发育以及脱髓鞘成年大脑中 OPC 的成熟都是必不可少的。
