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.

基底神经节的发育及其连接的形成复杂且较差 了解流程。基底神经节是运动功能、认知和语言不可或缺的一部分 发展以及社会和情绪调节。虽然一些基因已被确定在 基底神经节神经元规范，或在基底神经节疾病中，这些基因和其他基因如何调节 基底神经节连接的发展尚不清楚。进一步说，基底神经节的实际过程 发育过程中的轴突寻路尚未得到表征。我的假设是连通性 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育和遗传控制 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，该项目有三个具体目标： 目标 1. 开发分子和遗传标记以可视化纹状体和中间脑 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 这些原子核。为了研究它们的寻路，我生成了针对基底神经节的新型增强子系 神经元，包括 dlx(mini):gfp 和foxP2-enhancerA:egfp。 目标 2. 表征斑马鱼纹状体和 mesDA 神经元的正常轴突寻路 在开发过程中。我将使用增强gfp构建体和转基因系来描述 连接性，并将寻路与比率、狭缝、ephs 和 ephrins 的表达模式进行比较。 目标 3. 评估 robo、slit 和 ephlephrin 基因在纹状体和 mesDA 神经元寻路中的作用。 我将通过组合使用来测试这些基因家族不同成员的功能和效果 突变鱼系和吗啉。 临床意义：我们的结果将提高我们对基底神经节发育的理解 连接性，在神经发育和神经退行性疾病中受到影响。 摘要：这里描述的工作将是基底神经节轴突寻路的第一个描述， 表征连通性的发展及其遗传基础。我的结果将包括两者 基底神经节发育的描述性要素，以及特定基因作用的分析。 该项目包含一个结构完善的职业发展计划，得到了广泛支持 机构资源和国际知名导师，协助我在 K 期间进行过渡 授予独立终身教授职位。