Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.
Cellular and Tissue Genomics Department, Genentech, Inc., South San Francisco, California, USA.
Glia. 2024 Feb;72(2):289-299. doi: 10.1002/glia.24473. Epub 2023 Sep 28.
Myelination by oligodendrocytes is critical for fast axonal conduction and for the support and survival of neurons in the central nervous system. Recent studies have emphasized that myelination is plastic and that new myelin is formed throughout life. Nonetheless, the mechanisms that regulate the number, length, and location of myelin sheaths formed by individual oligodendrocytes are incompletely understood. Previous work showed that the lysosomal transcription factor TFEB represses myelination by oligodendrocytes and that the RagA GTPase inhibits TFEB, but the step or steps of myelination in which TFEB plays a role have remained unclear. Here, we show that TFEB regulates oligodendrocyte differentiation and also controls the length of myelin sheaths formed by individual oligodendrocytes. In the dorsal spinal cord of tfeb mutants, individual oligodendrocytes produce myelin sheaths that are longer than those produced by wildtype cells. Transmission electron microscopy shows that there are more myelinated axons in the dorsal spinal cord of tfeb mutants than in wildtype animals, but no significant change in axon diameter. In contrast to tfeb mutants, oligodendrocytes in rraga mutants produce shorter myelin sheaths. The sheath length in rraga; tfeb double mutants is not significantly different from wildtype, consistent with the antagonistic interaction between RagA and TFEB. Finally, we find that the GTPase activating protein Flcn and the RagCa and RagCb GTPases are also necessary for myelination by oligodendrocytes. These findings demonstrate that TFEB coordinates myelin sheath length and number during myelin formation in the central nervous system.
少突胶质细胞的髓鞘形成对于轴突的快速传导以及中枢神经系统中神经元的支持和存活至关重要。最近的研究强调了髓鞘形成的可塑性，即在整个生命过程中都会形成新的髓鞘。尽管如此，调节单个少突胶质细胞形成的髓鞘数量、长度和位置的机制仍不完全清楚。先前的工作表明，溶酶体转录因子 TFEB 抑制少突胶质细胞的髓鞘形成，而 RagA GTPase 抑制 TFEB，但 TFEB 发挥作用的髓鞘形成步骤仍不清楚。在这里，我们表明 TFEB 调节少突胶质细胞分化，并且还控制单个少突胶质细胞形成的髓鞘长度。在 tfeb 突变体的背根脊髓中，单个少突胶质细胞产生的髓鞘比野生型细胞产生的长。透射电子显微镜显示，tfeb 突变体的背根脊髓中有更多的髓鞘轴突，但轴突直径没有明显变化。与 tfeb 突变体相反，rraga 突变体中的少突胶质细胞产生较短的髓鞘。rraga; tfeb 双突变体的鞘长度与野生型无显著差异，这与 RagA 和 TFEB 之间的拮抗相互作用一致。最后，我们发现 GTPase 激活蛋白 Flcn 和 RagCa 和 RagCb GTPases 也是少突胶质细胞髓鞘形成所必需的。这些发现表明，TFEB 在中枢神经系统的髓鞘形成过程中协调髓鞘长度和数量。
