The RNA Binding Protein FMRP Promotes Myelin Sheath Growth

项目摘要 神经系统中的细胞是高度极化的，细胞间的接触发生在离细胞很远的地方。 身体。少突胶质细胞在大小不一的独立轴突上产生大量的髓鞘 生理学，这突出了在个体末端产生髓鞘膜的显著灵活性 远端突起。此外，髓鞘形成是一个依赖活动的过程，可以增强神经元功能和 是学习和记忆所必需的，这表明少突胶质细胞对神经回路的重要贡献 发展。有趣的是，髓鞘缺陷和髓鞘基因表达改变在脆性脑病中已被发现。 X综合征、自闭症谱系障碍和一系列神经发育障碍，这些都表明 少突胶质细胞在疾病发病机制中的重要作用。我们最近的证据表明，RNA 结合蛋白脆性x智力低下蛋白(FMRP)是髓鞘生长所必需的 依赖于mRNA翻译调控的机制。然而，协调初始阶段的基因 髓鞘生长尚不清楚，其mRNA调控的亚细胞机制也不清楚。 少突胶质细胞。我们假设，FMRP调控着基因的本地化和翻译 少突胶质细胞中髓鞘的生长。我们将使用斑马鱼验证这一假设，基于我们的 在发育中的神经细胞类型特异性可视化和基因表达操作方面的专业知识 系统。我们的实验计划包括两个部分。首先，我们将确定FMRP结合在 靶向mRNAs。其次，我们将可视化预测构成髓鞘基础的mRNAs的亚细胞定位。 鞘生长和操控目标基因在活斑马鱼少突胶质细胞中的特异性表达。这 该项目有可能发现初始髓鞘生长所需的必要基因，并将为 为进一步研究亚细胞活性依赖的mRNA调控机制奠定基础 髓鞘形成过程中的翻译。

Project Summary Cells in the nervous system are highly polarized and intercellular contacts take place at great distance from cell bodies. Oligodendrocytes produce numerous myelin sheaths on independent axons of variable size and physiology, which highlights remarkable flexibility in the production of myelin membrane at the tips of individual distal processes. Moreover, myelination is an activity-dependent process that enhances neuronal function and is required for learning and memory, indicating essential contributions of oligodendrocytes to neural circuit development. Interestingly, myelin deficiencies and altered myelin gene expression have been noted in Fragile X Syndrome, autism spectrum disorders, and a wide array of neurodevelopmental disorders, which indicate essential roles for oligodendrocytes in disease pathogenesis. Our recent evidence indicates that the RNA binding protein fragile x mental retardation protein (FMRP) is required for myelin sheath growth in a mechanism that is dependent on the translational regulation of mRNA. However, the genes coordinating initial myelin sheath growth are unknown, as are the subcellular mechanisms of mRNA regulation in oligodendrocytes. We hypothesize that FMRP regulates the localization and translation of mRNAs required for myelin sheath growth in oligodendrocytes. We will test this hypothesis using zebrafish, building upon our expertise in cell-type specific visualization and manipulation of gene expression in the developing nervous system. Our experimental plan has two parts. First, we will identify the precise location of FMRP binding on target mRNAs. Second, we will visualize the subcellular localization of mRNAs predicted to underlie myelin sheath growth and manipulate target gene expression specifically in oligodendrocytes of living zebrafish. This project has the potential to uncover the essential genes required for initial myelin sheath growth and will lay the foundation for future investigations into the mechanism of subcellular activity-dependent regulation of mRNA translation during myelination.