Characterization and Genetic Analysis of Basal Ganglia Axon Pathfinding

基底节轴突寻路的特征和遗传分析

• 批准号: 8242817
• 负责人: Josh Leitch Bonkowsky
• 金额: $ 18.62万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242817
• 关键词: Affect; Antibodies; Axon; Basal Ganglia; Basal Ganglia Diseases; Behavioral; Biological Models; Cell Nucleus; Central Nervous System Part; Cognitive; Complex; Corpus striatum structure; DNA; Development; Development Plans; Disease; Drug Exposure; Elements; Embryo; Emotional; Enhancers; Ephrins; Faculty; Family; Fertilization; Fishes; Gene Family; Gene Mutation; Genes; Genetic; Genetic Markers; Genomics; Globus Pallidus; Green Fluorescent Proteins; Hour; Human; Imagery; In Situ; K-Series Research Career Programs; Label; Language Development; Mammals; Mentors; Molecular Genetics; Motor; Movement; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Pattern; Positioning Attribute; Process; Reagent; Regulation; Research Personnel; Resources; Role; Structure; Structure of subthalamic nucleus; Substantia nigra structure; Synapses; Techniques; Testing; Tissues; Transgenic Organisms; Wheat Germ Agglutinins; Work; Zebrafish; addiction; base; career development; clinically significant; developmental genetics; dopaminergic neuron; emotion regulation; genetic analysis; improved; interest; member; molecular marker; mutant; nervous system development; novel; social; tissue culture

The development of the basal ganglia and the formation of their connections are complex and poorly understood processes. The basal ganglia are integral to motor function, to cognitive and language development, and to social and emotional regulation. While some genes have been identified with roles in basal ganglia neuron specification, or in diseases of the basal ganglia, how these and other genes regulate the development of basal ganglia connectivity is not known. Further, the actual process of basal ganglia axon pathfinding during development has not been characterized. My hypothesis is that connectivity of the striatum and the mesodiencephalic dopaminergic (mesDA) neurons is controlled by the path- finding gene families of the robos, the s//fs, and the ephslephrins. My long-term objective is to characterize the development and genetic control of basal ganglia connectivity, using zebrafish (Danio rerio) as a model system. In order to explore the development of basal ganglia connections, this project has three specific aims: Aim 1. Develop molecular and genetic markers to visualize striatal and mesodiencephalic dopaminergic (mesDA) neurons and their axons. I am using in situ gene markers and antibodies to label these nuclei. To study their pathfinding, I have generated novel enhancer lines specific for basal ganglia neurons, including dlx(mini):gfp and foxP2-enhancerA:egfp. Aim 2. Characterize the normal axon pathfinding of the zebrafish striatum and mesDA neurons during development. I will use enhancergfp constructs and transgenic lines to describe the development of connectivity, and compare the pathfinding to the expression patterns of the ratios, slits, ephs, and ephrins. Aim 3. Evaluate the role of robo, slit, and ephlephrin genes in striatal and mesDA neuron pathfinding. I will test the function and effects of different members of these gene families by using a combination of mutant fish lines and morpholinos. Clinical Significance: Our results will improve our understanding of the development of basal ganglia connectivity, which is affected in neurodevelopmental and neurodegenerative disorders. Summary: The work described here will be the first description of axon pathfinding of the basal ganglia, characterizing both the development of connectivity and its genetic basis. My results will include both descriptive elements of basal ganglia development, as well as analyses of the role of specific genes. This project consists of a well-structured career development plan, extensively supported with institutional resources and an internationally known mentor, to assist me with the transition during the K award to an independent tenure-track faculty position.

基底神经节的发展及其连接的形成很复杂且很差 理解过程。基底神经节是运动功能不可或缺的，认知和语言 发展以及社会和情感调节。虽然已经确定了某些基因在 基底神经神经元规范或基底神经节的疾病，这些基因和其他基因如何调节 基底神经节连通性的发展尚不清楚。此外，基底神经节的实际过程 发育过程中的轴突探路尚未表征。我的假设是 纹状体和中脑多巴胺能（MESDA）神经元受路径控制 寻找机器人，S // FS和Ephslephrins的基因家族。 我的长期目标是表征基底神经节的发展和遗传控制 连接性，使用斑马鱼（Danio Rerio）作为模型系统。 为了探索基底神经节连接的发展，该项目具有三个特定的目标： 目标1。开发分子和遗传标记以可视化纹状体和介导型 多巴胺能（MESDA）神经元及其轴突。我正在使用原位基因标记和抗体来标记 这些核。为了研究他们的探路，我已经产生了针对基底神经节的新型增强剂线 神经元，包括DLX（MINI）：GFP和FOXP2-ENHANCERA：EGFP。 AIM 2。表征斑马鱼纹状体和MESDA神经元的正常轴突路径 在开发过程中。我将使用EnhancerGFP构造和转基因线来描述 连通性，并将途径调节与比率，狭缝，EPHS和Ephrins的表达模式进行比较。 AIM 3。评估Robo，Slit和Ephlephrin基因在纹状体和MESDA神经元途径中的作用。 我将通过使用的组合来测试这些基因家族的不同成员的功能和影响 突变的鱼类线和吗啡。 临床意义：我们的结果将提高我们对基底神经节发展的理解 连通性，在神经发育和神经退行性疾病中受到影响。 摘要：此处描述的工作将是基底神经节轴突路径的第一个描述， 表征连通性的发展及其遗传基础。我的结果将包括 基础神经节发育的描述性要素，以及特定基因作用的分析。 该项目由结构良好的职业发展计划组成，并得到了广泛的支持 机构资源和国际知名的导师，以协助我在K期间的过渡 授予独立的终身教师职位。