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.

项目概要 神经系统的一个共同特征是，它们最初神经元数量过多且连接过度，最初 产生过多的突触连接。接下来是关键的改造时期 从而去除无关神经元或突触连接的子集，以优化功能 成人的神经系统。细胞的消除和突触的修剪是神经元协调的过程 和神经胶质细胞。选择特定的连接或单元进行消除似乎涉及到之间的对话 神经元和神经胶质细胞，神经系统碎片的清除主要是通过吞噬细胞进行的 胶质细胞。先前的研究强调，神经系统使用多种分子和 识别吞没目标的机制，这似乎是针对具体情况的。但仍存在重大差距 根据我们对神经元如何识别自己进行重塑以及神经胶质细胞如何识别这些死亡的了解 或修剪神经元。研究这些过程可能会让我们更好地理解机制 潜在的神经发育障碍，例如自闭症谱系障碍和精神分裂症。我们实验室有 采用果蝇作为模型系统有几个原因，包括强大的遗传工具和 其重塑时期之一——变态的刻板性质。通过转录组分析 吞噬星形胶质细胞，我鉴定出跨膜免疫球蛋白超家族基因无边界。我的 初步数据表明，Bdl 在星形胶质细胞早期吞噬期高度表达。 变态。有趣的是，无边界（Bdl）和已知的吞噬受体 Draper（MEGF10 在哺乳动物中）导致星形胶质细胞吞噬突触和神经突的强烈抑制。 BDL 已经 描述为与一种名为 Turtle 的密切相关蛋白质相互作用，我的初步数据进一步表明 Turtle 专门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 适当的吞没目标。在本研究的目标 1 中，我将表征星形胶质细胞中的 Bdl 表达，探索 Bdl 和 Draper 之间的遗传相互作用，并确定 Bdl 的哪些域对于吞噬至关重要 活动。在目标 2 中，我将 1) 定义 Bdl、Turtle 和 Draper 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和 3) 确定亚细胞定位 Turtle 让我探索 Turtle 作为指定神经突吞噬的分子标签。我的作品有 有可能定义星形胶质细胞吞噬机制的两个新组件（Bdl 和 Turtle），探索如何 他们与 Draper/MEGF10 融合，并将 Turtle 识别为神经突/突触特异性分子标签，可直接 指导星形胶质细胞吞噬活动。这项工作将极大地增进我们对分子的理解 神经元重塑过程中神经元-胶质细胞信号传导的基础，这对于我们理解和治疗至关重要 人类神经发育障碍。