Molecular Mechanisms of Axon Branching in Synaptic Development

突触发育中轴突分支的分子机制

• 批准号: 8078193
• 负责人: Le Ma
• 金额: $ 34.73万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078193
• 关键词: Afferent Neurons; Axon; Biochemical; Biological Assay; Biological Neural Networks; Brain; Cell physiology; Coupled; Cues; Cyclic GMP; DNA Sequence Rearrangement; Data; Defect; Development; Disease; Dominant-Negative Mutation; Ensure; Etiology; Genes; Genetic; Goals; Growth; Health; Image; In Vitro; Injury; Knockout Mice; Knowledge; Life; Link; Mediating; Mediator of activation protein; Microtubule Polymerization; Microtubules; Modeling; Molecular; Morphology; Multiple Partners; Mus; Mutant Strains Mice; NOS1 gene; Natural regeneration; Nerve Regeneration; Neurons; Pathway interactions; Pattern; Peripheral; Phosphorylation; Phosphotransferases; Plastics; Process; Protein Kinase; RNA Interference; Regulation; Research; Rodent; Role; Sensory; Signal Pathway; Signal Transduction; Site; Solid; Spinal Ganglia; Stroke; Structure of trigeminal ganglion; Synapses; Testing; axon growth; axon guidance; base; cGMP production; extracellular; in vivo; insight; interstitial; mutant; nervous system disorder; novel; receptor; response

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to investigate the molecular and cellular basis of axon branching, an important process in making synaptic connections and establishing neural networks. We will use a combination of molecular, cellular and genetic approaches to characterize key molecular pathways and identify the signaling mechanisms underlying the regulation of axon branching. The knowledge obtained from this study will not only help understand brain development, but also provide new insights into the molecular basis of many neurological disorders as well as how to promote nerve regeneration after stroke and injury.

描述（由申请人提供）：轴突分支允许神经元与多个伙伴进行通信，并有助于建立形态和功能上不同的神经网络。为了确保正确的突触连接，分支受到信号通路的严格调节，这些信号通路允许环境线索指示轴突何时何地产生分支。拟议研究的长期目标是研究这种调节的分子和细胞基础，了解它如何有助于突触连接的初始发育和随后的塑性重排，并提供有关如何在损伤后再生新分支和功能连接的见解。以啮齿动物感觉神经元背根神经节和三叉神经节的刻板轴突分支的发育为模型，我们发现了一条涉及分泌分子 Slit 促进轴突分支的细胞外信号通路。此外，我们的初步研究表明cGMP途径为分支调节提供了细胞内信号机制。使用原代感觉神经元培养物和基因敲除小鼠，我们提出以下三个目标来进一步表征 cGMP 信号传导的作用：1）使用体内分析将 cGMP 信号传导建立为调节多样化但刻板的感觉轴突分支发育的通用信号传导机制； 2) 确定感觉轴突分支中介导cGMP活性的下游信号机制； 3）确定轴突分支的空间和时间控制的细胞机制。这些目标应该有助于建立调节轴突分支的独特信号通路，并填补我们对突触连接重要过程理解的主要空白。此外，由于突触稳定性的丧失是许多神经系统疾病的标志，因此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新的见解。公共健康相关性：拟议研究的目标是研究轴突分支的分子和细胞基础，轴突分支是建立突触连接和建立神经网络的重要过程。我们将结合分子、细胞和遗传学方法来表征关键分子途径，并确定轴突分支调节背后的信号传导机制。从这项研究中获得的知识不仅有助于了解大脑发育，而且还为许多神经系统疾病的分子基础以及如何促进中风和损伤后的神经再生提供新的见解。