Molecular Mechanisms of Axon Branching in Synaptic Development

项目总结/摘要 轴突分支允许神经元与多个伙伴进行通信， 建立形态和功能上不同的神经网络。 以确保适当 在突触连接中，分支受到信号通路的严格调节， 环境线索来指示轴突何时何地形成分支。 长期目标 这项研究的目的是研究这种调节的分子和细胞基础， 了解它如何有助于最初的发展和随后的塑料 重新排列突触连接，并提供关于如何再生新的 损伤后的分支和功能连接。 利用啮齿类感觉神经元的刻板轴突分支的发育， 背根神经节和三叉神经节作为模型，我们已经确定了一个 分泌分子Slit参与的细胞外信号通路促进轴突生长 分支 此外，我们的初步研究表明，cGMP途径 为分支调节提供细胞内信号传导机制。 使用原代 感觉神经元培养和敲除小鼠，我们提出以下三个目标，以进一步 表征cGMP信号传导的作用：1）使用体内分析来建立cGMP信号传导， 一种调节多样化但刻板的发展的一般信号机制 感觉轴突分支; 2）识别介导cGMP的下游信号传导机制 活动的感觉轴突分支; 3）确定细胞机制的基础空间 以及轴突分支的时间控制。 这些目标应该有助于建立一个明确的信号 调节轴突分支的途径，并填补了我们对轴突分支的理解中的一个主要空白。 突触连接的重要过程。 此外，由于突触稳定性的丧失， 是许多神经系统疾病的标志，我们对这一基本过程的研究应该 为这些疾病的病因学提供了新的见解。

Project Summary/Abstract Axon branching allows a neuron to communicate with multiple partners and helps establish morphologically and functionally distinct neural networks. To ensure proper synaptic connections, branching is tightly regulated by signaling pathways that allow environmental cues to instruct axons when and where to make branches. The long term goal of the proposed research is to investigate the molecular and cellular basis of this regulation, understand how it contributes to the initial development and the subsequent plastic rearrangement of synaptic connections, and provide insights into how to regenerate new branches and functional connections after injury. Using the development of stereotypic axonal branches of rodent sensory neurons from the dorsal root ganglion and trigeminal ganglion as models, we have identified an extracellular signaling pathway involving the secreted molecule Slit in promoting axon branching. In addition, our preliminary studies have demonstrated that the cGMP pathway provides an intracellular signaling mechanism for branching regulation. Using primary sensory neuron cultures and knockout mice, we propose the following three aims to further characterize the role of cGMP signaling: 1) use in vivo analysis to establish cGMP signaling as a general signaling mechanism in regulating the development of diverse yet stereotypic sensory axon branches; 2) identify the downstream signaling mechanism mediating the cGMP activity in sensory axon branching; 3) determine the cellular mechanism underlying the spatial and temporal control of axon branching. These aims should help establish a distinct signaling pathway in regulating axon branching and fill in a major gap in our understanding of an important process in making synaptic connections. In addition, since loss of synaptic stability is the hallmark of many neurological disorders, our study of this fundamental process should provide new insights into the etiology of these diseases.