How do glia remodel the nervous system?

神经胶质细胞如何重塑神经系统？

• 批准号: 10464236
• 负责人: Rachel Yvette De La Torre
• 金额: $ 4.68万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-06 至 2024-10-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464236
• 关键词: Adult; Animals; Apoptosis; Astrocytes; Biological Assay; Biological Metamorphosis; Biological Models; Cell Compartmentation; Cell Surface Receptors; Cells; Cessation of life; Data; Defect; Development; Drosophila genus; Excision; Failure; Genes; Genetic; Goals; Human; Immunoglobulins; Individual; Integral Membrane Protein; Knock-out; Knowledge; Larva; Lead; Mammals; Mediating; Methods; Modeling; Molecular; Names; Nature; Nervous system structure; Neuraxis; Neurites; Neurodevelopmental Disorder; Neuroglia; Neurons; Neuropil; Pathway interactions; Phagocytes; Phagocytosis; Play; Process; Proteins; RNA Interference; Research; Role; Schizophrenia; Signal Transduction; Specific qualifier value; Specificity; Stereotyping; Synapses; System; Testing; Turtles; Visual system structure; Work; autism spectrum disorder; cell type; fly; human disease; in vivo; insight; knock-down; neuronal cell body; neuronal circuitry; neurotransmission; novel; receptor; response; sensory input; tool; transcriptomics

Project Summary A common feature of nervous systems is that they are initially overpopulated with neurons and over-wired, initially generating an excessive number of synaptic connections. This is followed by an essential period of remodeling whereby a subset of extraneous neurons or synaptic connections are removed in order to optimize function in the adult nervous system. The elimination of cells and pruning of synapses is a process coordinated by neurons and glia. The selection of specific connections or cells for elimination seems to involve a conversation between neurons and glia, and the clearance of debris from the nervous system is performed predominantly by phagocytic glial cells. Previous research has highlighted that the nervous system uses a diversity of molecules and mechanisms to identify engulfment targets, which appear to be context-specific. However, major gaps still exist in our knowledge of how neurons identify themselves to be remodeled and how glial cells recognize these dying or pruning neurons. Studying these processes can potentially lead us to a better understanding of mechanisms underlying neurodevelopmental disorders such as Autism Spectrum Disorders and Schizophrenia. Our lab has employed Drosophila as a model system for several reasons including the powerful genetic tools and the stereotyped nature of one of its remodeling periods—metamorphosis. Through transcriptomic profiling in phagocytic astrocytes, I identified the transmembrane immunoglobulin superfamily gene borderless. My preliminary data suggests that Bdl is highly expressed in astrocytes during engulfment periods early in metamorphosis. Interestingly, loss of both Borderless (Bdl) and the known engulfment receptor Draper (MEGF10 in mammals) resulted in strong suppression of astrocyte engulfment of synapses and neurites. Bdl has been described to interact with a closely related protein named Turtle, and my preliminary data further suggests Turtle is specifically localized to neurites and synapses, and excluded from the cell body (the only compartment of the cell that astrocytes do not engulf). Turtle may therefore act as a molecular tag for astrocytes to recognize appropriate engulfment targets. In Aim 1 of this study, I will characterize Bdl expression in astrocytes, explore genetic interactions between Bdl and Draper, and determine which domains of Bdl are essential for engulfment activity. In Aim 2, I will 1) define genetic interactions between Bdl, Turtle, and Draper, 2) determine the cell autonomy of Bdl and Turtle in the remodeling of corazonin neurons and 3) determine the subcellular localization of Turtle positing me to explore Turtle as a molecular tag for specifying neurites for engulfment. My work has the potential to define two novel components of the astrocytic engulfment machinery, (Bdl and Turtle), explore how they converge with Draper/MEGF10, and identify Turtle as a neurite/synapse-specific molecular tag that directly directs astrocyte engulfment activity. This work will significantly advance our understanding of the molecular basis of neuron-glia signaling during neuronal remodeling, which will be essential for us to understand and treat neurodevelopmental disorders in humans.

项目摘要 神经系统的一个共同特征是，它们最初是过度填充神经元和过度连接，最初 产生过多的突触连接。接下来是一个重要的重塑时期 从而去除无关神经元或突触连接的子集，以优化神经元的功能。 成人神经系统细胞的消除和突触的修剪是由神经元协调的过程 和胶质细胞。选择特定的连接或细胞进行消除似乎涉及到 神经元和神经胶质，并且从神经系统清除碎片主要通过吞噬细胞进行。 神经胶质细胞以前的研究已经强调，神经系统使用多种分子， 确定吞噬目标的机制，这些机制似乎是针对具体情况的。然而，仍然存在重大差距 在我们对神经元如何识别自己被重塑以及神经胶质细胞如何识别这些死亡的知识中， 或修剪神经元。研究这些过程可能会使我们更好地理解机制 潜在的神经发育障碍，如自闭症谱系障碍和精神分裂症。我们的实验室 使用果蝇作为模型系统有几个原因，包括强大的遗传工具和 定型性是其重塑期之一--变态。通过转录组学分析， 吞噬星形胶质细胞，我确定了跨膜免疫球蛋白超家族基因无边界。我 初步数据表明，Bdl在星形胶质细胞吞噬早期高度表达， 变态有趣的是，无边界（Bdl）和已知的吞噬受体德雷珀（MEGF 10）的丢失， 在哺乳动物中）导致对星形胶质细胞吞噬突触和神经突的强烈抑制。BDL已经 它被描述为与一种名为Turtle的密切相关的蛋白质相互作用，我的初步数据进一步表明Turtle 特异性地定位于神经突和突触，并被排除在细胞体之外（细胞体的唯一隔室）。 星形胶质细胞不吞噬的细胞）。因此，海龟可能充当星形胶质细胞识别的分子标签 合适的吞噬目标在本研究的目的1中，我将描述Bdl在星形胶质细胞中的表达，探索 Bdl和德雷珀之间的遗传相互作用，并确定Bdl的哪些结构域是吞噬所必需的 活动在目标2中，我将1）定义Bdl、Turtle和德雷珀之间的遗传相互作用，2）确定细胞 Bdl和Turtle在corazonin神经元重塑中的自主性; 3）确定亚细胞定位 让我探索海龟作为一个分子标签来指定吞噬的神经突。我的工作 潜在的定义星形胶质细胞吞噬机制的两个新的组成部分，（Bdl和海龟），探索如何 他们与德雷珀/MEGF 10汇合，并将Turtle鉴定为神经突/突触特异性分子标记， 指导星形胶质细胞吞噬活动。这项工作将大大推进我们对分子生物学的理解。 神经元重塑过程中神经胶质细胞信号传导的基础，这将是我们理解和治疗 神经发育障碍