Mechanisms of development and maintenance of neuronal architecture

神经元结构的发育和维持机制

• 批准号: RGPIN-2017-06553
• 负责人: Bénard, Claire
• 金额: $ 2.91万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=645116
• 关键词: Mechanisms; development; maintenance; neuronal; architecture

***BACKGROUND: During the development of the nervous system, neurons migrate through complex environments to connect to their targets, ensuring that neural circuits are properly wired to function. After its initial assembly, the neuronal architecture that was laid out during embryogenesis needs to persist during subsequent development, in the face of the addition of neurons into the existing circuits and the physical stress exerted by growth and body movements. Whereas much research has identified key guidance cues and receptors that instruct migrating neurons, how the cellular responses to the cues are orchestrated in time and space during development is unclear. Similarly, it remains largely unexplored how the neuronal architecture that is established during embryogenesis is maintained during subsequent development. Our research aims to understand how the nervous system gets wired and how it is subsequently maintained ensuring continued connectivity and function.*** Using the powerful model organism C. elegans, we have identified novel and specific roles for heparan sulfate proteoglycans in modulating axon guidance signals during development. We have also identified a battery of “neuronal maintenance” mutants whose nervous systems initially develop normally but later become abnormally wired.******MAIN OBJECTIVE: The goal of this project is to elucidate the molecular mechanisms underlying both (a) the guidance of migrations during the assembly of the nervous system, and (b) the long-term maintenance of neuronal architecture during subsequent growth and maturation. ******SPECIFIC OBJECTIVES: NSERC funding is requested for elucidating novel roles of heparan sulfate proteoglycans in axon guidance, and for identifying and studying novel neuronal maintenance molecules, in accordance with the following specific aims:*** 1. Elucidate the mechanism by which LON-2/glypican modulates netrin signals in axon guidance.*** 2. Study the separate role of a second glypican, GPN-1, in axon guidance.*** 3. Determine the role of two novel neuronal maintenance genes nema-1 and nema-2 that we have identified in our forward genetic screens for neuronal maintenance defective mutants.*** 4. Identify additional regulators of neuronal maintenance.******CONCLUSION: This research program is an excellent opportunity for increasing our general understanding of nervous system development and the long-term maintenance of neuronal structure and function. Given the evolutionary conservation between C. elegans and vertebrates, we expect that our research will uncover general principles underlying the development and maintenance of neural circuits, and thus have significant and long-lasting impact on the fields of developmental neurobiology and neuroscience.**

* 背景：在神经系统的发育过程中，神经元在复杂的环境中迁移，以连接到它们的目标，确保神经回路正确连接以发挥功能。初始组装后，面对向现有回路中添加神经元以及生长和身体运动施加的物理压力，胚胎发生期间布置的神经元架构需要在后续发育过程中持续存在。虽然许多研究已经确定了指导迁移神经元的关键指导线索和受体，但在发育过程中，细胞对这些线索的反应如何在时间和空间上进行协调尚不清楚。类似地，在胚胎发生期间建立的神经元结构如何在随后的发育期间维持，在很大程度上仍未探索。我们的研究旨在了解神经系统是如何连接的，以及它随后是如何维持的，以确保持续的连接和功能。 利用功能强大的模式生物C. elegans，我们已经确定了硫酸乙酰肝素蛋白多糖在发育过程中调节轴突导向信号的新的和特定的作用。我们还发现了一系列“神经元维持”突变体，它们的神经系统最初发育正常，但后来变得异常。主要目的：本项目的目标是阐明（a）神经系统组装过程中迁移的指导和（B）随后生长和成熟过程中神经元结构的长期维持的分子机制。** 具体目标：要求NSERC资助阐明硫酸乙酰肝素蛋白聚糖在轴突导向中的新作用，并根据以下具体目标鉴定和研究新型神经元维持分子：* 1.阐明LON-2/磷脂酰肌醇蛋白聚糖在轴突导向中调节netrin信号的机制。 2.研究第二种磷脂酰肌醇蛋白聚糖GPN-1在轴突导向中的单独作用。 3.确定两个新的神经元维持基因nema-1和nema-2的作用，这两个基因是我们在神经元维持缺陷突变体的正向遗传筛选中发现的。 4.确定神经元维持的其他调节因子。**结论：这项研究计划是一个很好的机会，增加我们对神经系统发育和神经元结构和功能的长期维持的一般理解。考虑到C.我们希望我们的研究将揭示神经回路发育和维持的一般原理，从而对发育神经生物学和神经科学领域产生重大而持久的影响。