How do glia remodel the nervous system?

项目摘要 神经系统的一个共同特征是，最初它们的神经元数量过多，并且最初过度连接 产生过多的突触连接。紧随其后的是重塑的关键时期。 借此移除外来神经元或突触连接的子集，以便优化 成人的神经系统。细胞的清除和突触的修剪是由神经元协调的过程 还有神经胶质细胞。选择要消除的特定连接或细胞似乎涉及到 神经元和神经胶质细胞，从神经系统清除碎片主要是通过吞噬细胞完成的 神经胶质细胞。先前的研究已经强调，神经系统使用多种分子和 确定吞没目标的机制，这似乎是特定于具体情况的。然而，仍然存在重大差距。 在我们关于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 或者修剪神经元。研究这些过程可能会使我们更好地理解这些机制 潜在的神经发育障碍，如自闭症、谱系障碍和精神分裂症。我们的实验室有 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 它的重塑时期之一的刻板印象--变形。通过转录剪裁分析 吞噬星形胶质细胞后，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，在星形胶质细胞的早期吞噬阶段，BDL高表达。 蜕变。有趣的是，无边界(BDL)和已知的吞噬受体Draper(MEGF10)的缺失 在哺乳动物中)导致星形胶质细胞吞噬突触和神经突起的强烈抑制。BDL一直是 被描述为与一种名为海龟的密切相关蛋白质相互作用，我的初步数据进一步表明海龟 特异性地定位于神经突起和突触，并排除在细胞体(细胞的唯一隔室 星形胶质细胞不会吞噬的细胞)。因此，海龟可能是星形胶质细胞识别的分子标签 适当的吞噬目标。在这项研究的目标1中，我将表征BDL在星形胶质细胞中的表达，探索 Bdl和Draper之间的遗传交互作用，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、海龟和Draper之间的遗传交互作用，2)确定细胞 BDL和海龟在Corazine神经元重塑中的自主性及3)决定亚细胞定位 海龟让我把海龟作为分子标签来指定吞噬神经突起。我的作品有 定义星形细胞吞噬机制的两个新组件(BDL和Turtle)的可能性，探索如何 它们与Draper/MEGF10融合，并将海龟识别为神经突起/突触特异的分子标记，直接 引导星形胶质细胞吞噬活动。这项工作将极大地促进我们对分子的理解 神经元重塑过程中神经元-胶质细胞信号的基础，这对我们理解和治疗是必不可少的 人类的神经发育障碍。

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.