Mechanisms of development and maintenance of neuronal architecture

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，连接到它们的目标，确保神经回路正确地连接到功能。在初始组装之后，胚胎形成的神经元结构需要在随后的发育中持续存在，以面对现有电路中神经元的增加以及生长和身体运动所施加的物理压力。尽管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是如何在时间和空间上进行协调的尚不清楚。同样，在胚胎发生期间建立的神经元结构如何在随后的发育中维持，在很大程度上仍未被探索。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。***利用强大的模式生物秀丽隐杆线虫，我们已经确定了硫酸肝素蛋白聚糖在发育过程中调节轴突引导信号中的新的和特定的作用。我们还发现了一组“神经元维持”突变体，它们的神经系统最初发育正常，但后来变得异常连接。******主要目的：本项目的目标是阐明(a)神经系统组装过程中的迁移指导和(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资助阐明硫酸肝素蛋白多糖在轴突引导中的新作用，并根据以下具体目标识别和研究新的神经元维持分子：阐明LON-2/glypican在轴突引导中调节网络信号的机制。* * * 2。研究另一种典型蛋白GPN-1在轴突引导中的单独作用。* * * 3。确定两个新的神经元维持基因nema-1和nema-2的作用，我们已经在我们的神经维持缺陷突变体的前向遗传筛选中确定。* * * 4。确定神经元维持的其他调节因子。******结论：这个研究项目是一个很好的机会，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。考虑到秀丽隐杆线虫和脊椎动物之间的进化守恒，我们期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

***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.**