Nerve Growth Cone Locomotion

轴突生长过程中最重要的部分可能是其顶端的结构，即生长锥。神经生长锥对于定向轴突生长是必不可少的。它们是复杂的感觉运动机器，通过细胞表面受体或离子通道通透性的变化对环境线索做出反应。它们使用信号转导通路在局部处理这些信息，这些信号转导通路调节负责驱动通过环境向前推进的运动机制。关于整合信息并调节其对运动的影响的具体机制，我们知之甚少。虽然信号转导通路已经被牵连，它一直很难链接这些途径的具体效应机制的运动，持续随着时间的推移。一个有效的机制是肌球蛋白产生的力。肌球蛋白活性具有多种作用，包括控制生长锥形状变化和产生驱动向前推进的牵引力。这是一 生长锥运动的重要效应，可能是必不可少的方向的变化， 进步。我的总体目标是确定负责调节生长锥运动的各种肌球蛋白，了解特定环境线索刺激的途径如何控制肌球蛋白活性，以及所产生的力如何与细胞外环境耦合以提供牵引力。我建议，肌球蛋白II是最重要的肌球蛋白确定在生长锥调节运动和产生牵引力。我将通过消除肌球蛋白II的活性，然后测量包括牵引力在内的运动的关键方面来测试这个提议。我还计划确定参与生长锥肌球蛋白II调节的主要途径。结合这些结果将提供框架，了解生长锥运动的分子基础，以及环境因素如何刺激特定的途径来调节这种运动。这对于理解发育过程中神经元回路的形成以及成功神经再生所需的机制至关重要。

Probably the most important part of the growing axon is the structure at its tip, the growth cone. Nerve growth cones are essential for directed axonal outgrowth. They are complex sensory-motor machines that respond to environmental cues through cell surface receptors or changes in ion channel permeability. They locally process this information using signal transduction pathways that regulate the motility mechanism responsible for driving forward advancement through the environment. Relatively little is known about the specific mechanisms that integrate the information and regulate its affect on motility. Although signal transduction pathways have been implicated, it has been difficult to link these pathways to specific effecter mechanisms of motility that persist over time. One effecter mechanism is the generation of force by myosin. Myosin activity has multiple roles that include the control of growth cone shape changes and the generation of traction force that drives forward advancement. It is an important effecter of growth cone motility that may be essential for changes in direction of advancement. My overall goal is to identify the various myosins responsible for modulating growth cone motility, understand how pathways that are stimulated by specific environmental cues control myosin activity and how the force that is developed is coupled to the extracellular environment to provide traction force. I propose that myosin II is the most important of the myosins identified in growth cones for regulating motility and producing traction force. I will test this proposal by eliminating the activity of myosin II and then measuring key aspects of motility including traction force. I also plan to identify the major pathways involved in growth cone myosin II regulation. Combined these results will provide the framework for understanding the molecular basis of growth cone motility and how environmental cues stimulate specific pathways to regulate this motility. This is essential for understanding the formation of neuronal circuitry during development and the mechanisms required for successful nerve regeneration.