Mechanisms of neuron-oligodendrocyte precursor cell interactions

髓鞘是一种由称为少突胶质细胞的特殊胶质细胞产生的多层膜。 (OL)在脊椎动物中枢神经系统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(OPC)，神经元和OPC之间的功能相互作用 OL以及神经元和OPC之间的联系对中枢神经系统的功能和健康至关重要。一个专门的但非常 鲜为人知的神经元和OPC之间的相互作用发生在神经元-OPC突触：几乎所有 OPC在突触后与神经元形成突触。OPC在许多方面不同于成熟神经元：它们 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这样的问题：神经元-OPC突触是否适应OPC独特的 生物学，并使用不同的突触发育机制。尽管之前的EM和 电生理特征，几乎对OPC中突触的发育一无所知， 控制神经元-OPC突触形成的分子机制，以及通过神经元-OPC的信号转导 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，它们之间的关系 突触与髓鞘形成，并探索调节这些过程的潜在分子机制。 斑马鱼为活体成像提供了无与伦比的光学清晰度，并提供了快速遗传的强大工具 操纵。我们已经确认了两种突触后支架的存在，PSD-95和Gen，在 神经元-OPC突触，并产生了新的工具来标记包含这些支架的突触在OPC。我们的 初步结果提示OPC中独特的突触组装和拆解机制，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，我们将确定和 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 还将使用细胞特异的敲除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)。我们的工作可以一起定义以前未知的函数 神经元-OPC突触并揭示了介导神经元-神经胶质细胞相互作用的重要机制 脊椎动物中枢神经系统。

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.