Mathews Emily S, Appel Bruce
Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045.
Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045
J Neurosci. 2016 Jul 20;36(29):7628-39. doi: 10.1523/JNEUROSCI.0726-16.2016.
Myelin, which ensheaths and insulates axons, is a specialized membrane highly enriched with cholesterol. During myelin formation, cholesterol influences membrane fluidity, associates with myelin proteins such as myelin proteolipid protein, and assembles lipid-rich microdomains within membranes. Surprisingly, cholesterol also is required by oligodendrocytes, glial cells that make myelin, to express myelin genes and wrap axons. How cholesterol mediates these distinct features of oligodendrocyte development is not known. One possibility is that cholesterol promotes myelination by facilitating signal transduction within the cell, because lipid-rich microdomains function as assembly points for signaling molecules. Signaling cascades that localize to cholesterol-rich regions of the plasma membrane include the PI3K/Akt pathway, which acts upstream of mechanistic target of rapamycin (mTOR), a major driver of myelination. Through manipulation of cholesterol levels and PI3K/Akt/mTOR signaling in zebrafish, we discovered that mTOR kinase activity in oligodendrocytes requires cholesterol. Drawing on a combination of pharmacological and rescue experiments, we provide evidence that mTOR kinase activity is required for cholesterol-mediated myelin gene expression. On the other hand, cholesterol-dependent axon ensheathment is mediated by Akt signaling, independent of mTOR kinase activity. Our data reveal that cholesterol-dependent myelin gene expression and axon ensheathment are facilitated by distinct signaling cascades downstream of Akt. Because mTOR promotes cholesterol synthesis, our data raise the possibility that cholesterol synthesis and mTOR signaling engage in positive feedback to promote the formation of myelin membrane.
The speed of electrical impulse movement through axons is increased by myelin, a specialized, cholesterol-rich glial cell membrane that tightly wraps axons. During development, myelin membrane grows dramatically, suggesting a significant demand on mechanisms that produce and assemble myelin components, while it spirally wraps axons. Our studies indicate that cholesterol is necessary for both myelin growth and axon wrapping. Specifically, we found that cholesterol facilitates signaling mediated by the PI3K/Akt/mTOR pathway, a powerful driver of myelination. Because mTOR promotes the expression of genes necessary for cholesterol synthesis, cholesterol formation and PI3K/Akt/mTOR signaling might function as a feedforward mechanism to produce the large amounts of myelin membrane necessary for axon ensheathment.
髓鞘包裹并隔离轴突，是一种富含胆固醇的特殊膜结构。在髓鞘形成过程中，胆固醇影响膜的流动性，与髓鞘蛋白脂蛋白等髓鞘蛋白结合，并在膜内组装富含脂质的微结构域。令人惊讶的是，制造髓鞘的神经胶质细胞少突胶质细胞表达髓鞘基因并包裹轴突也需要胆固醇。胆固醇如何介导少突胶质细胞发育的这些不同特征尚不清楚。一种可能性是胆固醇通过促进细胞内信号转导来促进髓鞘形成，因为富含脂质的微结构域充当信号分子的组装点。定位于质膜富含胆固醇区域的信号级联包括PI3K/Akt途径，该途径在雷帕霉素作用靶点（mTOR）上游起作用，mTOR是髓鞘形成的主要驱动因素。通过操纵斑马鱼体内的胆固醇水平和PI3K/Akt/mTOR信号，我们发现少突胶质细胞中的mTOR激酶活性需要胆固醇。结合药理学和拯救实验，我们提供证据表明mTOR激酶活性是胆固醇介导的髓鞘基因表达所必需的。另一方面，胆固醇依赖性轴突包裹由Akt信号介导，与mTOR激酶活性无关。我们的数据表明，Akt下游不同的信号级联促进了胆固醇依赖性髓鞘基因表达和轴突包裹。由于mTOR促进胆固醇合成，我们的数据提出了胆固醇合成和mTOR信号参与正反馈以促进髓鞘膜形成的可能性。
髓鞘是一种特殊的、富含胆固醇的神经胶质细胞膜，紧密包裹轴突，可提高电冲动在轴突中的移动速度。在发育过程中，髓鞘膜显著生长，这表明对产生和组装髓鞘成分的机制以及其螺旋状包裹轴突的机制有重大需求。我们的研究表明，胆固醇对于髓鞘生长和轴突包裹都是必需的。具体而言，我们发现胆固醇促进了由PI3K/Akt/mTOR途径介导的信号传导，该途径是髓鞘形成的强大驱动因素。由于mTOR促进胆固醇合成所需基因的表达，胆固醇形成和PI3K/Akt/mTOR信号可能作为一种前馈机制，以产生轴突包裹所需的大量髓鞘膜。
