Characterization and Genetic Analysis of Basal Ganglia Axon Pathfinding

基底节的发育和它们之间的联系的形成是复杂的和差的。 了解流程。基底节是运动功能、认知功能和语言功能的组成部分 发展，以及社会和情绪调节。虽然一些基因已经被鉴定为在 基底节神经元规范，或在基底节疾病中，这些基因和其他基因是如何调节的 基底节连通性的发展尚不清楚。此外，基底节的实际突起 轴突在发育过程中的寻路还没有被描述出来。我的假设是， 纹状体和中间脑多巴胺能神经元受以下通路控制： 寻找机器人、S和麻黄素的基因家族。 我的长期目标是研究基底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。 为了探索基底节连接的发展，该项目有三个具体目标： 目的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。为了研究他们的路径发现，我已经产生了针对基底节的新的增强子系列 神经元，包括DLX(Mini)：GFP和Foxp2-EnhancerA：EGFP。 目的2.斑马鱼纹状体和MesDA神经元的正常轴突通路特征 在开发过程中。我将使用Enhancergfp构建和转基因系来描述 连通性，并将路径发现与比率、狭缝、Ephs和Eparin的表达模式进行比较。 目的3.评价ROBO、SIIT和Ephlephin基因在纹状体和MesDA神经元通路中的作用。 我将使用以下组合来测试这些基因家族的不同成员的功能和效果 变异的鱼线和吗啡。 临床意义：我们的结果将提高我们对基底节发育的理解 连接性，这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对基底节轴突路径的第一次描述， 描述了连通性的发展及其遗传基础。我的结果将包括这两个 基底节发育的描述性要素，以及特定基因的作用分析。 该项目包括一个结构良好的职业发展计划，并得到广泛的支持 机构资源和一位国际知名的导师，帮助我在K 授予一个独立的终身教职教师职位。

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.