Oligodendrocyte development and myelin sheath formation are regulated by the antagonistic interaction between the Rag-Ragulator complex and TFEB.
Oligodendrocyte development and myelin sheath formation are regulated by the antagonistic interaction between the Rag-Ragulator complex and TFEB.
复制标题
少突胶质细胞的发育和髓鞘的形成受 Rag-Ragulator 复合物和 TFEB 之间的拮抗相互作用的调节。
作者：
Bouchard,EllenL;Meireles,AnaM;Talbot,WilliamS
少突胶质细胞的髓鞘形成对于快速轴突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，髓鞘形成是可塑性的，新的髓鞘在整个生命过程中形成。尽管如此，调节由单个少突胶质细胞形成的髓鞘的数量、长度和位置的机制还不完全清楚。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，并且RagA GTfB抑制TFEB，但是TFEB在髓鞘形成中起作用的一个或多个步骤仍然不清楚。在这里，我们表明，TFEB调节少突胶质细胞的分化，也控制髓鞘的长度形成的个别少突胶质细胞。在tfeb突变体的脊髓背侧，单个少突胶质细胞产生的髓鞘比野生型细胞产生的髓鞘长。透射电镜观察发现，突变体脊髓背角有髓轴突比野生型多，但轴突直径无明显变化。与突变体相反，少突胶质细胞突变体产生较短的髓鞘。鞘长inrraga; tfebdouble突变体与野生型没有显著差异，这与RagA和TFEB之间的拮抗相互作用一致。最后，我们发现GT3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在中枢神经系统中髓鞘形成期间协调髓鞘长度和数量。
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 oftfebmutants, 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 oftfebmutants than in wildtype animals, but no significant change in axon diameter. In contrast totfebmutants, oligodendrocytes inrragamutants produce shorter myelin sheaths. The sheath length inrraga;tfebdouble 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.