Institute for Myelin and Glia Exploration, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, New York 14203.
Institute for Myelin and Glia Exploration, 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. 2023 May 17;43(20):3614-3629. doi: 10.1523/JNEUROSCI.1383-22.2023. Epub 2023 Mar 28.
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 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. 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.
为了验证转铁蛋白（Tf）循环对少突胶质细胞发育和功能具有独特重要性的假设，我们使用 Cre/LoxP 系统在雄性和雌性小鼠的少突胶质前体细胞（OPC）中破坏 Tf 受体（Tfr）基因的表达。这种消融导致通过 Tf 循环进行铁摄取的消除，但保留其他 Tf 功能完好无损。特异性地在 NG2 或 Sox10 阳性 OPC 中缺乏 Tfr 的小鼠表现出低髓鞘形成表型。OPC 分化和髓鞘形成均受到影响，并且 Tfr 缺失导致 OPC 铁吸收受损。具体而言，Tfr cKO 动物的大脑中少突胶质细胞轴突的髓鞘数量减少，成熟少突胶质细胞数量减少。相比之下，成年小鼠中 Tfr 的消融既不影响成熟少突胶质细胞也不影响髓鞘合成。在 Tfr cKO OPC 中进行的 RNA-seq 分析显示，涉及 OPC 成熟、髓鞘形成和线粒体活性的调节基因失调。皮质 OPC 中 Tfr 的缺失也破坏了 mTORC1 信号通路的活性，该通路对于基因转录和结构性线粒体基因的表达至关重要。此外，在铁储存通过删除铁蛋白重链而被破坏的 OPC 中进行了 RNA-seq 研究。这些 OPC 显示与铁转运、抗氧化活性和线粒体活性相关的基因异常调节。因此，我们的结果表明，Tf 循环在出生后发育过程中 OPC 中的铁稳态中起核心作用，并表明 Tfr 介导的铁摄取和铁蛋白中的铁储存对于能量产生、线粒体活性和出生后 OPC 的成熟都是至关重要的。通过特异性敲除少突胶质细胞前体细胞（OPC）中的转铁蛋白受体（Tfr），我们已经确定，通过 Tf 循环进行的铁摄取对于 OPC 铁稳态和这些细胞在中枢神经系统出生后发育中的正常功能至关重要。此外，RNA-seq 分析表明，Tfr 铁摄取和铁蛋白铁储存对于适当的 OPC 线粒体活性、能量产生和成熟都是至关重要的。
