Mechanism of Growth Cone Turning in Diffusible Gradients

神经系统的精确连接依赖于轴突的引导生长 纤维连接到它们的特定目标进行突触连接。轴突寻路取决于 在发育中的轴突顶端的运动性生长锥体，它感觉并对 在复杂多变的环境中导航的各种细胞外信号。 这项拟议的研究旨在阐明一种新的信号放大机制 使生长锥体能够感知引导线索的浅梯度，以生成高度 极化的基于肌动蛋白的运动性。这项工作将利用一个定义明确的神经元 生长锥体翻转检测的培养系统，复杂的高分辨率成像 技术，细胞内分子的直接操作，以及分子和 细胞成分的药理操作。中心假设是 基于磷脂酰肌醇的信号放大使生长锥能够感觉到浅 引导线索的梯度，以产生定向响应。拟议的研究将 进一步研究肌醇磷脂的分子机制 信号放大。我们的目标是从机械上理解经济增长是如何 视锥将时空分布的细胞外线索转换为不同的方向 反应，导致特定突触连接的形成。 细胞感知环境和确定方向的能力以及 接近细胞外刺激，然后是正确的运动，是 包括神经发育在内的许多发育事件。定向细胞运动也 是许多病理事件的基础，尤其是癌细胞转移。建议数 本研究以神经生长锥为模型，研究神经生长锥信号转导机制。 在轴突寻路过程中，生长锥体的定向感觉是基础。结果是 这项研究不仅将为深入了解人类免疫缺陷的分子机制提供重要的依据 轴突引导，但也扩展了我们关于定向细胞运动的知识 许多生理和病理事件。因此这项工作直接关系到 公共卫生。

Precise wiring of the nervous system depends on the guided growth of axonal fibers to their specific targets for synaptic connections. Axon pathfinding depends on the motile growth cone at the tip of developing axons, which senses and responds to a variety of extracellular signals to navigate through a complex and changing environment. The proposed study aims to elucidate a novel signal amplification mechanism that enables growth cones to sense shallow gradients of guidance cues to generate highly polarized actin-based motility. The work will take advantage of a well-defined neuronal culture system for growth cone turning assays, sophisticated high-resolution imaging techniques, direct manipulation of intracellular molecules, and molecular and pharmacological manipulation of cellular components. The central hypothesis is that phosphoinositide-based signal amplification enables the growth cone to sense shallow gradients of guidance cues to generate directional responses. The proposed study will further investigate the molecular mechanisms underlying the phosphoinositide-based signal amplification. The goal is to gain a mechanistic understanding on how a growth cone translates spatiotemporally distributed extracellular cues to distinct directional responses, leading to the formation of specific synaptic connections. The cell’s ability to sense the environment and to determine the direction and proximity of an extracellular stimulus, followed by correct movement, is fundamental for many developmental events including neural development. Directed cell motility also underlies many pathological events, especially cancer-cell metastasis. The proposed study uses nerve growth cones as the model to study the signaling mechanisms that underlie the directional sensing of growth cones during axon pathfinding. The results from this study will not only provide significant insights into the molecular mechanisms of axon guidance, but also extend our knowledge concerning directed cell movement in many physiological and pathological events. Therefore the work is directly relevant to public health.