Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045, and Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37232.
J Neurosci. 2014 Feb 26;34(9):3402-12. doi: 10.1523/JNEUROSCI.4587-13.2014.
Myelin membrane, which ensheaths axons, has an unusually high amount of cholesterol. Cholesterol influences membrane fluidity and assembles lipid-rich microdomains within membranes, and some studies have shown that cholesterol is important for myelination. How cholesterol influences the development and differentiation of oligodendrocytes, glial cells that make myelin, is not known nor is clear whether isoprenoids, which also are products of the cholesterol biosynthetic pathway, contribute to myelination. Through a forward genetic screen in zebrafish we discovered that mutation of hmgcs1, which encodes an enzyme necessary for isoprenoid and cholesterol synthesis, causes oligodendrocyte progenitor cells (OPCs) to migrate past their target axons and to fail to express myelin genes. Drawing on a combination of pharmacological inhibitor and rescue experiments, we provide evidence that isoprenoids and protein prenylation, but not cholesterol, are required in OPCs to halt their migration at target axons. On the other hand, cholesterol, but not isoprenoids, is necessary both for axon ensheathment and myelin gene expression. Our data reveal that different products of the cholesterol biosynthetic pathway have distinct roles in oligodendrocyte development and that they together help to coordinate directed migration, axon wrapping, and gene expression.
髓鞘膜包裹轴突，其胆固醇含量异常高。胆固醇会影响膜的流动性，并在膜内组装富含脂质的微区，一些研究表明胆固醇对髓鞘形成很重要。胆固醇如何影响少突胶质细胞（形成髓鞘的神经胶质细胞）的发育和分化尚不清楚，也不清楚异戊烯基等胆固醇生物合成途径的产物是否有助于髓鞘形成。通过对斑马鱼的正向遗传筛选，我们发现 hmgcs1 突变（该基因编码异戊烯基和胆固醇合成所必需的酶）会导致少突胶质前体细胞（OPC）迁移到其靶轴突之外，并导致其无法表达髓鞘基因。通过药理学抑制剂和挽救实验的综合运用，我们提供的证据表明，异戊烯基和蛋白质异戊烯化（而非胆固醇）是 OPC 停止在靶轴突迁移所必需的。另一方面，胆固醇（而非异戊烯基）对于轴突包绕和髓鞘基因表达都是必需的。我们的数据表明，胆固醇生物合成途径的不同产物在少突胶质细胞发育中具有不同的作用，它们共同有助于协调定向迁移、轴突包裹和基因表达。
