Mechanisms of Retinal Axon Pathfinding

视网膜轴突寻路机制

基本信息

批准号：
6844640
负责人：
Chi-Bin Chien
金额：
$ 33.64万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-02-04 至 2007-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): For growing axons to find their targets in the developing brain, their growth cones must respond to both attractive and repulsive signals in the environment. It has recently been shown that growth cones can modulate their responses to particular signal, even switching from attraction to repulsion; however, it is not known if this occurs in vivo. The zebrafish visual system is uniquely suited for studying how growth cones integrate positive and negative signals in vivo, and testing how their responses to signals change as they pathfind. The proposed experiments study the roles of two classes of guidance cues, Slits and netrins, in retinal axon pathfinding. Slits are thought to signal repulsively through the Astray/Robo2 receptor, while netrins are thought to signal attractively through the DCC receptor. Slit/Robo2 and netrin/DCC are both known to guide retinal axons, but their roles in different parts of the pathway are unknown. A combination of forward-genetic, reverse-genetic, and transgenic approaches will be used to perturb Slit/Robo2 and netrin/DCC signaling in vivo, to test where in the retinal pathway these signals are important, and to test whether their roles change over the course of the pathway. The zebrafish retinotectal system not only allows visualization of retinal axons in vivo with exquisite resolution, but also allows precisely targeted perturbations of their in vivo environment. The results and techniques developed here will help lead to a comprehensive understanding of all the signals that guide retinal axon growth, and how these different signals interact. In summary, this project will illuminate where, when, and how the guidance of zebrafish retinal axons requires Slit/Robo2 and netrin/DCC signaling. The resulting knowledge of genetic and developmental mechanisms will be important for understanding human diseases, such as albinism, that affect optic axon guidance. This knowledge will also be critical for designing therapies to reverse optic nerve degeneration. More generally, this project will test broad principles of axon guidance which are important for understanding the wiring of the nervous system and the basis of inherited neurological disease.

描述（由申请人提供）：为了让生长的轴突在发育中的大脑中找到它们的目标，它们的生长锥必须对环境中的吸引和排斥信号做出反应。最近的研究表明，生长锥可以调节它们对特定信号的反应，甚至从吸引转变为排斥。然而，尚不清楚这是否发生在体内。斑马鱼视觉系统特别适合研究生长锥体内如何整合正负信号，并测试它们在寻路时对信号的反应如何变化。拟议的实验研究了两类引导线索（狭缝和网络蛋白）在视网膜轴突寻路中的作用。狭缝被认为通过 Astray/Robo2 受体发出排斥性信号，而 netrins 被认为通过 DCC 受体发出吸引性信号。已知 Slit/Robo2 和 netrin/DCC 都能引导视网膜轴突，但它们在通路不同部分中的作用尚不清楚。正向遗传、反向遗传和转基因方法的组合将用于扰乱体内 Slit/Robo2 和 netrin/DCC 信号传导，以测试这些信号在视网膜通路中的重要位置，并测试它们的角色是否发生变化。路径的过程。斑马鱼视网膜顶盖系统不仅可以以精细的分辨率对体内视网膜轴突进行可视化，还可以对其体内环境进行精确的有针对性的扰动。这里开发的结果和技术将有助于全面了解引导视网膜轴突生长的所有信号，以及这些不同信号如何相互作用。总之，该项目将阐明斑马鱼视网膜轴突的引导何时、何地以及如何需要 Slit/Robo2 和 netrin/DCC 信号传导。由此产生的遗传和发育机制知识对于理解影响视轴突引导的人类疾病（例如白化病）非常重要。这些知识对于设计逆转视神经变性的疗法也至关重要。更一般地说，该项目将测试轴突引导的广泛原理，这对于理解神经系统的连接和遗传性神经系统疾病的基础非常重要。