Cytoskeleton dynamics and axon behaviour: a role for Wnt signalling

大脑功能的形成需要组装适当的神经连接。在发育过程中，神经细胞(神经元)延伸被称为轴突的长过程，这些过程广泛地生长以寻找它们的目标组织。沿着它们的轨迹，轴突会遇到一些信号，这些信号会引起不同的反应，比如吸引、停顿或排斥。轴突或生长锥体的尖端对这些信号特别敏感。例如，某些信号会导致停顿、延长和转弯。这些不同的反应是通过这些细胞外信号与神经元内的骨架(细胞骨架)进行‘对话’和修改的能力来实现的。这种细胞骨架是由动态聚合物形成的，这种聚合物在长度、组织和生长方向上发生变化，使神经细胞能够对环境的变化做出快速反应。尽管在识别大量轴突引导线索方面取得了很大进展，但关于这些细胞外线索调节轴突行为的机制，特别是这些信号如何改变轴突中的细胞骨架，人们知之甚少。我们的实验室一直在研究WNTS，即突触靶标释放的分子，在神经连接形成中的功能。当轴突遇到WNT蛋白时，当轴突暂停、形成分支并改变其形状时，WNT会引起轴突行为的深刻变化。在这些变化之后，WNTS通过带来释放神经递质所需的组件来刺激突触的形成。这项拨款提案涉及WNT分子改变轴突行为的机制，以及与细胞骨架变化的关系。由于我们主要关注轴突的再生，我们的研究将为损伤后神经修复的可能治疗策略提供新的线索。

The formation of a functional brain requires the assembly of appropriate nerve connections. During development, nerve cells (neurons) extend long processes called axons that grow extensively in search for their target tissue. Along their trajectory axons encounter a number of signals that elicit different responses such as attraction, pausing or repulsion. The tip of the axon or growth cone is particularly sensitive to these signals. For example, certain signals induce pausing, extension, and turning. These different responses are accomplished by the ability of these extracellular cues to 'talk' to and modify the skeleton (cytoskeleton) inside neurons. This cytoskeleton is formed by dynamic polymers that change in length, organization and direction of growth allowing nerve cells to respond quickly to changes in the environment. Although great progress has been made in the identification of large number of axon guidance cues, little is known about the mechanisms by which these extracellular cues modulate the behaviour of axons and particularly how these signals change the cytoskeleton in axons. Our laboratory has been studying the function of Wnts, molecules released by synaptic targets, in the formation of nerve connections. Wnts induce profound changes in the behaviour of axons as axons pause, form branches and change their shape when they encounter Wnt proteins. Following these changes, Wnts stimulate the formation of synapses by bringing components necessary for the release of neurotransmitters. This grant proposal addresses the mechanisms by which Wnt molecules change the behaviour of axons and the relationship with changes in the cytoskeleton. As we mainly focus on regenerating axons, our studies will new shed light into possible therapeutic strategies that can be used for nerve repair after injury.