Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
University of Edinburgh/MS Society Centre for MS Research, MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, UK.
Dev Cell. 2018 Nov 5;47(3):319-330.e5. doi: 10.1016/j.devcel.2018.10.003.
Myelin allows for fast and efficient axonal conduction, but much remains to be determined about the mechanisms that regulate myelin formation. To investigate the genetic basis of myelination, we carried out a genetic screen using zebrafish. Here, we show that the lysosomal G protein RagA is essential for CNS myelination. In rraga mutant oligodendrocytes, target genes of the lysosomal transcription factor Tfeb are upregulated, consistent with previous evidence that RagA represses Tfeb activity. Loss of Tfeb function is sufficient to restore myelination in RagA mutants, indicating that hyperactive Tfeb represses myelination. Conversely, tfeb single mutants exhibit ectopic myelin, further indicating that Tfeb represses myelination during development. In a mouse model of de- and remyelination, TFEB expression is increased in oligodendrocytes, but the protein is localized to the cytoplasm, and hence inactive, especially during remyelination. These results define essential regulators of myelination and may advance approaches to therapeutic remyelination.
髓鞘允许轴突快速有效地传导，但关于调节髓鞘形成的机制还有很多需要确定。为了研究髓鞘形成的遗传基础，我们使用斑马鱼进行了遗传筛选。在这里，我们表明溶酶体 G 蛋白 RagA 对于中枢神经系统的髓鞘形成是必不可少的。在 rraga 突变型少突胶质细胞中，溶酶体转录因子 Tfeb 的靶基因上调，与 RagA 抑制 Tfeb 活性的先前证据一致。TFEB 功能丧失足以恢复 RagA 突变体中的髓鞘形成，表明过度活跃的 Tfeb 抑制髓鞘形成。相反，tfeb 单突变体表现出异位髓鞘，进一步表明 Tfeb 在发育过程中抑制髓鞘形成。在脱髓鞘和再髓鞘的小鼠模型中，少突胶质细胞中的 TFEB 表达增加，但该蛋白定位于细胞质，因此处于非活性状态，尤其是在再髓鞘过程中。这些结果定义了髓鞘形成的必需调节剂，并可能推进治疗性再髓鞘的方法。
