Nerve Growth Cone Locomotion

可能生长轴突最重要的部分是其顶端的结构，即生长锥体。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-马达机器，通过细胞表面受体或离子通道通透性的变化对环境提示做出反应。它们使用信号转导通路在本地处理这些信息，这些信号转导通路调节负责推动环境向前推进的动力机制。对于整合信息并调节其对运动的影响的具体机制，人们知之甚少。尽管信号转导通路已经被涉及，但很难将这些通路与特定的运动效应机制联系起来，这些机制随着时间的推移而存在。一种有效的机制是肌球蛋白产生的力。肌球蛋白的活性具有多种作用，包括控制生长锥体形状的变化和产生驱使前进的牵引力。这是一个 生长锥体运动的重要影响因素，可能是改变生长方向所必需的 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，了解受特定环境线索刺激的通路如何控制肌球蛋白活动，以及所产生的力如何耦合到细胞外环境以提供牵引力。我认为肌球蛋白II是生长锥体中发现的最重要的肌球蛋白，用于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性的关键方面来测试这一提议。我还计划确定与生长激素肌球蛋白II调控有关的主要途径。结合这些结果，将为理解生长锥运动的分子基础以及环境线索如何刺激特定的途径来调节这种运动提供框架。这对于理解发育过程中神经元回路的形成以及成功的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.