The molecular basis for target selection in the central nervous system by sensory axons

大脑的正常功能取决于神经细胞之间的特定连接。这些连接是在发育中的胚胎中建立的，当时神经细胞发出长的突起-轴突-向它们的突触目标生长。轴突如何从发育中的大脑中数百万个选择中选择正确的目标是未知的。更好地了解这个问题将有助于我们开发治疗方法，以帮助再生轴突在大脑或脊髓损伤后重新建立正确的连接。我们建议使用一个简单的模型系统，果蝇的胚胎，找到参与神经元靶向识别过程的分子-“轴突靶向”分子-并研究它们如何工作。果蝇可以用高等动物不可能的方式进行基因操纵。此外，它的神经系统的简单性意味着我们可以以高度的精确度确定单个神经细胞的连接。在我们项目的第一部分，我们将检查果蝇胚胎，这些胚胎携带着疑似编码靶向分子的基因突变。我们将用染料对这些胚胎中的单个感觉神经细胞进行染色，以揭示它们在大脑中轴突的解剖结构。如果特定突变体大脑中的感觉轴突异常终止，则受影响的基因可能编码轴突靶向分子。在研究的第二部分，我们将使用两种方法研究候选轴突靶向分子的功能。首先，我们将试图确定该分子是否作用于感觉轴突或其靶细胞。其次，我们将使用延时显微镜来研究感觉轴突的归巢行为如何在突变胚胎中受到影响。这些研究的结果将使我们更接近这个问题的答案：轴突如何识别大脑中特定的靶细胞？

The normal function of the brain depends upon the specific connections that nerve cells make with each other. These connections are set up in the developing embryo when nerve cells send out long processes - axons - which grow towards their synaptic targets. How axons select their correct targets from amongst the millions of alternatives in the developing brain is unknown. A better understanding of this problem will help us develop therapies to assist regenerating axons re-establish correct connections following injury to the brain or spinal cord. We propose to use a simple model system, the embryo of the fruitfly Drosophila, to find molecules that are involved in this process of neuron target recognition - ' axon targeting' molecules - and to study how they work. Drosophila can be genetically manipulated in ways not possible in higher animals. Furthermore the simplicity of its nervous system means that we can determine the connections of individual nerve cells with a high degree of precision. In the first part of our project, we will examine Drosophila embryos that carry mutations in genes suspected to code for targeting molecules. We will stain individual sensory nerve cells in these embryos with dyes to reveal the anatomy of their axons in the brain. If sensory axons terminate abnormally in the brain of a given mutant, the affected gene is likely to code for an axon targeting molecule. In the second part of the study, we will investigate the functions of candidate axon targeting molecules using two approaches. Firstly, we will seek to determine whether the molecule acts in the sensory axons or in their target cells. Secondly, we will use time-lapse microscopy to study how the homing behaviour of the sensory axons is affected in mutant embryos. The results of these studies will lead us closer to an answer to the question: How do axons recognise their specific target cells in the brain?