Slit Fragments Generate Diversity in Axon Guidance Signals

轴突引导是研究发育中的神经如何对外部环境做出反应 信号。已经识别出的导航信号数量非常少，引发了 大脑的复杂性是如何产生的问题。一种解决方案是，单一的 配体可以通过不同的受体或通过不同的受体以不同的方式发出信号 通过改变受体结合的过程。Sit是一种巨大的分泌性蛋白质， 通常使用ROBO受体排斥生长中的轴突。缝隙被切割成两个片段， Sit-N和Sit-C，它们在神经系统中显示出新的生物活性，在 还有很多其他的纸巾。然而，缝隙碎片的作用存在争议。狭缝-N 片段包含Robo结合位点，并已被证明是排斥轴突在 体外培养系统等被认为是活跃的信号分子。多条线路 在果蝇体内的初步证据表明，只有全长(Sit-FL) 蛋白质排斥轴突。这项建议采用了体内分子遗传学方法对果蝇进行研究。 和小鼠来分离Sit-FL信号和狭缝片段的信号。这两个 系统将使我们能够解决Sit对轴突生长、轴突分支和 调节粘连(分束)。这项工作将使我们能够确定单个 信号可以实现不同的生物结果。拟议的工作对以下方面有影响 不同的领域，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.