Mechanisms of neuron-oligodendrocyte precursor cell interactions

神经元-少突胶质前体细胞相互作用的机制

• 批准号: 10153390
• 负责人: Kelly R Monk
• 金额: $ 23.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153390
• 关键词: Affect; Animals; Axon; Biology; CRISPR/Cas technology; Candidate Disease Gene; Cell Communication; Cell Differentiation process; Cell membrane; Cell physiology; Cells; Cellular biology; Demyelinating Diseases; Development; Electrophysiology (science); Embryo; Environment; Foundations; Future; Genes; Health; Health system; Homeostasis; Knowledge; Label; Lead; Learning Disorders; Length; Life; Location; Measures; Mediating; Membrane; Modeling; Molecular; Monitor; Multiple Sclerosis; Myelin; Myelin Sheath; Nervous System Physiology; Neuraxis; Neuroglia; Neurons; Oligodendroglia; Optics; Play; Process; Role; Signal Transduction; Spinal Cord; Synapses; System; Testing; Time; Transgenic Organisms; Work; Zebrafish; base; density; genetic manipulation; gephyrin; human disease; in vivo; in vivo imaging; knock-down; loss of function; myelination; nervous system development; neural circuit; neurotransmission; novel; oligodendrocyte myelination; oligodendrocyte precursor; postsynaptic; precursor cell; presynaptic density protein 95; repaired; response; scaffold; synaptogenesis; tool

The myelin sheath is a multilayered membrane generated by specialized glial cells called oligodendrocytes (OLs) that iteratively spiral their plasma membranes around axon segments in the vertebrate central nervous system (CNS). OLs derive from OL precursor cells (OPCs), and functional interactions between neurons and OLs as well as between neurons and OPCs are critical for CNS function and health. A specialized but very poorly understood interaction between neurons and OPCs occurs at the neuron-OPC synapse: nearly all OPCs form synapses postsynaptically to neurons. OPCs differ from mature neurons in many ways: they migrate, frequently remodel processes, and are capable of transforming their processes into myelin sheaths. These unique cellular features raise questions as to whether neuron-OPC synapses adapt to an OPC's unique biology and employ distinct mechanisms for synapse development. Despite previous EM and electrophysiological characterizations, almost nothing is known about synapse development in OPCs, the molecular mechanisms that govern neuron-OPC synapse formation, and how signaling via neuron-OPC synapses influences myelination. Here we propose to use zebrafish to investigate neuron-OPC synapse development, the relationship of these synapses to myelination, and to probe the underlying molecular mechanisms regulating these processes. Zebrafish provide unparalleled optical clarity for in vivo imaging and powerful tools for rapid genetic manipulations. We have identified the presence of two postsynaptic scaffolds, PSD-95 and gephyrin, at neuron-OPC synapses and generated new tools to label synapses containing these scaffolds in OPCs. Our preliminary results suggest unique synapse assembly and disassembly mechanisms in OPCs and highlight potential roles for synapses in OPC development and myelination. In this application, we will determine if and how neuron-OPC synapses are correlated with OPC differentiation and subsequent myelination (Aim 1). We will also employ cell-specific knockdown approaches to identify genes that are critical for synapse development and assess their roles in OPC biology (Aim 2). Together, our work can define previously unknown functions for neuron-OPC synapses and reveal important mechanisms that mediate neuron-glial interactions in the vertebrate CNS.

髓鞘是由称为少突胶质细胞的特化胶质细胞产生的多层膜 (OLs)它们在脊椎动物中枢神经的轴突节段周围反复螺旋其质膜 系统（CNS）。OL来源于OL前体细胞（OPCs），神经元和 OLs以及神经元和OPCs之间的相互作用对CNS功能和健康至关重要。一个专业的，但非常 神经元和OPC之间的相互作用发生在神经元-OPC突触：几乎所有 OPCs在突触后形成神经元的突触。OPCs在许多方面与成熟神经元不同： 迁移，经常重塑过程，并能够将其过程转化为髓鞘。 这些独特的细胞特征提出了一个问题，即神经元-OPC突触是否适应OPC的独特功能。 生物学并采用不同的突触发育机制。尽管此前EM和 尽管在电生理学特征方面，对OPCs中的突触发育几乎一无所知， 控制神经元-OPC突触形成的分子机制，以及如何通过神经元-OPC进行信号传导 突触影响髓鞘形成。 在这里，我们建议使用斑马鱼研究神经元-OPC突触的发育，这些之间的关系， 突触到髓鞘形成，并探索调节这些过程的潜在分子机制。 斑马鱼为体内成像提供了无与伦比的光学清晰度，并为快速遗传学研究提供了强大的工具。 操纵我们已经确定了两个突触后支架，PSD-95和桥蛋白的存在， 神经元-OPC突触，并产生了新的工具来标记OPC中含有这些支架的突触。我们 初步结果表明，独特的突触组装和拆卸机制，在OPC和强调 突触在OPC发育和髓鞘形成中的潜在作用。在本申请中，我们将确定是否和 神经元-OPC突触如何与OPC分化和随后的髓鞘形成相关（Aim 1）。我们 还将采用细胞特异性敲除方法来鉴定对突触发育至关重要的基因 并评估它们在OPC生物学中的作用（目标2）。总之，我们的工作可以定义以前未知的函数， 神经元-OPC突触，并揭示了介导神经元-胶质细胞相互作用的重要机制， 脊椎动物中枢神经系统