Role of the ubiquitin system in drosophila synaptogenesis

突触发生是神经细胞与其他细胞（如神经元和肌肉细胞）连接的过程，是神经系统和肌肉发育的关键事件。我们实验室最近的工作证明了泛素系统在调节神经系统发育和功能方面的重要作用，包括运动神经元，运动神经元是支配肌肉的神经细胞。泛素系统在控制蛋白质分解/稳定、运输和内吞作用中起关键作用，从而影响细胞中的大多数生化途径。泛素化级联中非常重要的酶是泛素连接酶，它负责底物识别和泛素附着。我们已经从包括果蝇（Drosophila, dNedd4）在内的几种生物中分离出了泛素连接酶Nedd4，并且最近发现它在果蝇的轴突引导和突触发生中起重要作用。我们的目标是了解dNedd4和泛素化如何调节突触发生。利用果蝇的生物化学和遗传方法，我们将研究调节dNedd4及其剪接变异体功能的信号转导途径，以及这些变异体在调节dNedd4靶蛋白commisless （Comm）和roundabout （Robo）中的作用，这些蛋白在果蝇轴突引导和突触发生中起关键作用。这些研究对于我们理解泛素系统的一般功能及其在神经系统中的作用非常重要，并且对我们了解与泛素系统的错误功能相关的越来越多的疾病，包括神经系统疾病，如帕金森病和阿尔茨海默病，具有重要意义。

Synaptogenesis is a process by which nerve cells connect to other cells, such as neurons and muscle cells, and is a key event in the development of the nervous system and muscles. Recent work from our lab demonstrated an essential role for the ubiquitin system in regulating nervous system development and function, including motoneurons, which are nerve cells that innervate muscles. The ubiquitin system plays a pivotal role in controlling protein breakdown/stability, trafficking and endocytosis, and thus affects most biochemical pathways in the cell. Very important enzymes in the ubiquitination cascade are the ubiquitin ligases, which are responsible for substrate recognition and ubiquitin attachment to them. We had isolated the ubiquitin ligase Nedd4 from several organisms, including the one from fruit flies (Drosophila, dNedd4), and shown recently that it is important for axon guidance and synaptogenesis in flies. Our goal is to understand how dNedd4 and ubiquitination regulate synaptogenesis. Using biochemical and genetic approaches in Drosophila, we will investigate the signal transduction pathways that regulate the function of dNedd4 and its splice variants, and the role of these variants in regulating the dNedd4 target proteins commissureless (Comm) and roundabout (Robo), which play a critical role in axon guidance and synaptogenesis in flies. These studies are important to our understanding of the function of the ubiquitin system in general and its role in the nervous system in particular, and have implications to our knowledge of the growing list of disorders associated with misguided function of the ubiquitin system, including neurological diseases such as Parkinson's and Alzheimer's.