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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

基本信息

批准号：
10307572
负责人：
Kelly R Monk
金额：
$ 19.25万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10307572
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

项目摘要

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殊神经胶质细胞产生的多层膜（OL）在脊椎动物中枢神经的轴突段周围迭代地螺旋其质膜系统（中枢神经系统）。 OL 源自 OL 前体细胞 (OPC)，神经元和 OL 之间的功能相互作用 OL 以及神经元和 OPC 之间的连接对于 CNS 功能和健康至关重要。一个专业但非常神经元和 OPC 之间的相互作用发生在神经元-OPC 突触处：几乎所有神经元和 OPC 之间的相互作用都鲜为人知。 OPC 在突触后形成神经元突触。 OPC 在很多方面与成熟神经元不同：迁移，经常重塑过程，并且能够将其过程转化为髓鞘。这些独特的细胞特征引发了神经元-OPC 突触是否适应 OPC 独特特性的问题。生物学并采用不同的突触发育机制。尽管之前的 EM 和电生理学特征，关于 OPC 中突触的发育几乎一无所知，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 发出信号突触影响髓鞘形成。在这里我们建议使用斑马鱼来研究神经元-OPC突触的发育，这些之间的关系突触到髓鞘形成，并探讨调节这些过程的潜在分子机制。斑马鱼为体内成像提供无与伦比的光学清晰度，并为快速遗传提供强大的工具操纵。我们已经确定了两种突触后支架的存在，PSD-95 和 gephyrin，神经元-OPC 突触并生成了新工具来标记 OPC 中包含这些支架的突触。我们的初步结果表明 OPC 具有独特的突触组装和拆卸机制，并强调突触在 OPC 发育和髓鞘形成中的潜在作用。在此应用程序中，我们将确定是否以及神经元-OPC 突触如何与 OPC 分化和随后的髓鞘形成相关（目标 1）。我们还将采用细胞特异性敲低方法来识别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）。我们的工作可以共同定义以前未知的功能神经元-OPC突触并揭示介导神经元-胶质细胞相互作用的重要机制脊椎动物的中枢神经系统。