Analysis of Novel Ligands for the Dscam Receptor in Axon Guidance

在发育中的胚胎中，不断生长的神经必须经过很长的距离才能找到它们的目标，并将神经系统连接起来。神经的单个纤维被称为轴突，了解轴突如何导航是非常有趣的，因为它解释了大脑和神经系统最初的复杂性是如何产生的。生长中的轴突对环境中的吸引或排斥信号作出反应；同样的线索也可以刺激整体增长。唐氏综合症细胞粘附分子（Dscam）基因存在于大多数具有神经系统的生物体中。出乎意料的是，Dscam允许轴突探测到已知的导航线索，并对它们做出反应。在这个提议中，驱动大部分工作的工作模型是，Dscam将这些提示解释为有吸引力的信号，并刺激轴突朝着这些提示生长。这个模型正在果蝇身上进行基因测试。果蝇的神经系统非常简单，可以观察单个轴突的生长，并分析当Dscam活性降低或缺失时轴突是如何受到影响的。从实验的结果将允许评估是否全部或部分模型是正确的。这项工作得到了组织培养细胞实验的支持，该实验研究了Dscam和线索如何在物理上相互作用。该项目为研究生和本科生提供最先进的遗传和分子生物学培训。这项研究的结果有望推进我们对果蝇以及包括脊椎动物脊髓在内的许多其他神经系统的轴突生长和导航方式的了解。

In the developing embryo, growing nerves have to navigate long distances to find their targets and to connect up the nervous system. The individual fibers of the nerves are known as axons, and understanding how axons navigate is of great interest as it explains how the initial complexity of the brain and nervous system arises. Growing axons respond to cues in their environment that can either be attractive or repulsive; the same cues can also stimulate overall growth. The Down Syndrome Cell Adhesion Molecule (Dscam) gene is present in most organisms with a nervous system. Dscam unexpectedly allows axons to detect well-known navigational cues and to respond to them. The working model that drives much of the work in this proposal is that Dscam interprets the cues as attractive signals and stimulates axon growth towards the cues. This model is being tested in the fruit fly Drosophila using a genetic approach. The fruit fly nervous system is simple enough to observe the growth of single axons and to analyze how axons are affected when Dscam activity is reduced or absent. The results from the experiments will allow evaluation of whether all or part of the model is correct. The work is supported by experiments on tissue culture cells examining how Dscam and the cues physically interact. The project provides state of the art genetic and molecular biology training for both graduate and undergraduate students. The results derived from this study are expected to advance our knowledge of how axons grow and navigate in the fruit fly, as well as in many other nervous systems including the vertebrate spinal cord.