Slit Fragments Generate Diversity in Axon Guidance Signals

轴突引导是研究发育中的神经如何响应外部刺激而导航的。 信号.已经确定的导航信号数量非常少， 大脑的复杂性是如何产生的一个解决方案是， 配体可以通过不同受体的存在以不同的方式发出信号， 通过处理改变受体结合。Slit是一种大的分泌蛋白， 通常用机器人受体排斥生长的轴突裂缝被切割成两个碎片， Slit-N和Slit-C在神经系统中显示新的生物活性， 许多其他组织。然而，裂缝碎片的作用是有争议的。Slit-N 片段含有Robo结合位点，并已被证明是排斥轴突在 因此被认为是活性信号分子。多行 在果蝇体内的初步证据表明，只有全长（狭缝FL） 蛋白质排斥轴突该建议采用了果蝇体内分子遗传学方法 和小鼠分离Slit-FL的信号传导与Slit片段的信号传导。这两个 系统将使我们能够解决Slit对轴突生长，轴突分支和 调节粘连（肌束震颤）。这项工作将使我们能够确定一个单一的 信号可以实现不同的生物学结果。拟议的工作对以下方面有影响： 广泛的领域，包括传染病，癌症和神经再生。

Axon guidance is the study of how developing nerves navigate in response to external signals. A remarkably small number of navigational signals have been identified, raising the question of how the complexity of the brain is generated. One solution is that a single ligand can signal in different ways either through the presence of different receptors or through processing that alters receptor binding. Slit is a large secreted protein that typically repels growing axons using Robo receptors. Slit is cleaved into two fragments, Slit-N and Slit-C, which display new biological activities in the nervous system and that in many other tissues. However, the role of the Slit fragments is controversial. The Slit-N fragment contains the Robo binding site and has been shown to be repel axons in in vitro culture systems and so is thought to be the active signaling molecule. Multiple lines of in vivo preliminary evidence in Drosophila suggest that only the full-length (Slit-FL) protein repels axons. This proposal takes an in vivo molecular genetic approach in flies and mice to separate the signaling of Slit-FL from that of the Slit fragments.These two systems will allow us to address the effects of Slit on axon growth, axon branching and regulated adhesion (fasciculation). This work will allow us to determine how a single signal can achieve different biological outcomes. The proposed work has implications for a diverse range of fields, including infectious disease, cancer and nerve regeneration.