How do glia remodel the nervous system?

神经胶质细胞如何重塑神经系统？

• 批准号: 10608973
• 负责人: Rachel Yvette De La Torre
• 金额: $ 4.77万
• 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/10608973
• 关键词: Adult; Animals; Apoptosis; Astrocytes; Axon; Biological Assay; Biological Metamorphosis; Biological Models; Cell Compartmentation; Cell Surface Receptors; Cells; Central Nervous System; Cessation of life; Data; Defect; Development; Drosophila genus; Excision; Exclusion; Failure; Genes; Genetic; Goals; Human; Immunoglobulins; Individual; Inflammation; Integral Membrane Protein; Knock-out; Knowledge; Larva; Mammals; Mediating; Membrane; Methods; Modeling; Molecular; Names; Nature; Nervous System; Neurites; Neurodevelopmental Disorder; Neuroglia; Neurons; Neuropil; Pathway interactions; Phagocytes; Phagocytosis; Process; Proteins; RNA Interference; Research; Role; Schizophrenia; Signal Transduction; Specific qualifier value; Specificity; Stereotyping; Synapses; System; Testing; Turtles; Visual System; Visualization; 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; transcriptomic profiling

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，它们最初被神经元和过度接线的人口过多，最初是 产生过多的突触连接。其次是重塑的必要时期 因此，删除了外部神经元或突触连接的子集，以优化功能 成人神经系统。消除细胞和突触修剪是由神经元协调的过程 和神经胶质。选择特定连接或细胞以消除的选择似乎涉及 神经元和神经胶质以及神经系统中碎屑的清除主要由吞噬细胞进行 神经胶质细胞。先前的研究强调，神经系统使用多种分子， 确定吞噬目标的机制，似乎是特定于上下文的。但是，主要差距仍然存在 在我们了解神经元如何识别自己的重塑以及神经胶质细胞如何识别这些垂死的情况下 或修剪神经元。研究这些过程可能会导致我们更好地理解机制 基本的神经发育障碍，例如自闭症谱系障碍和精神分裂症。我们的实验室有 使用果蝇作为模型系统的原因有几个原因，包括强大的遗传工具和 其重塑时期之一的定型性质 - 变形。通过转录组分析 吞噬的星形胶质细胞，我鉴定了跨膜免疫球蛋白超家族基因无边界。我的 初步数据表明，BDL在早期的吞噬期间在星形胶质细胞中高度表达 变态。有趣的是，丢失无边界（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没突触和神经运动。 BDL已经 描述的是与乌龟的紧密相关蛋白质相互作用，我的初步数据表明乌龟 专门定位于神经和突触，并从细胞体中排除（唯一的隔室 星形胶质细胞不会吞噬的细胞）。因此，乌龟可以充当星形胶质细胞识别的分子标签 适当的吞噬目标。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AIM 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神经元的重塑中的自主权，3）确定亚细胞定位 Turtle的象征，将我探索乌龟作为用于指定吞噬神经的分子标签。我的工作有 定义星形胶质细胞吞噬机械（BDL和Turtle）的两个新颖组成部分的潜力，探索 它们与draper/megf10收敛，并将乌龟视为神经/突触特异性的分子标签 指导星形胶质细胞吞噬活动。这项工作将大大提高我们对分子的理解 神经元重塑过程中神经胶质信号的基础，这对于我们了解和治疗至关重要 人类的神经发育障碍。