Drosophila Sensory Neuron Development

大脑中的连通性。在这项资助中，我们将解决果蝇神经突分支的问题。 神经突分支是所有动物中枢神经系统中形成连通性的关键过程之一。 了解神经突分支的分子机制将是重要的，不仅是为了 神经科学家有兴趣了解大脑发育，但也为临床医生迅速以下 发展利用未分化神经元移植治疗神经退行性疾病的治疗方法 疾病，如帕金森病或阿尔茨海默病。为了使这种移植有效， 如果能够操纵供体神经元与宿主神经元相互作用的方式， 微环境，并作为回应，形成分支的神经突，成为整合在主机的 电路果蝇提供了一个很好的模型系统，以解决在高水平的神经突起分支， 解决，因为丰富的分子遗传工具和事实，大脑的神经元落入 由相对少量的干细胞样成神经细胞产生的谱系。在工作中， 在上一个资助期，我们已经绘制了幼虫大脑谱系的示意图， 幼虫的投射路径。每个谱系的神经纤维束都经历了一个特征性的模式， 分支，这使得识别和处理它们成为可能。拟议的研究涉及 以下假设：（i）在皮层-神经堆边界集轴突和神经胶质之间的相互作用 分支点;（ii）在轴突内，分支点的设置取决于Par复合体，根据 (now扩展）的初步结果是本地化在未来的分支点;（iii）神经突之间的相互作用 和神经胶质细胞和随后的浓度的Par 3在分支点涉及钙粘蛋白介导的相互作用。 我们对这组假设的主要支持是观察到，减少三个因素中的每一个，神经胶质， Par和DECadherin在幼虫谱系中导致相似的表型，其包括近端 分支在目标#1中，我们将从结构和实验上研究神经突-神经胶质细胞的相互作用。目标#2 和#3我们提出了两个分子途径的实验和遗传分析，Par复合物和 钙粘蛋白粘附复合物，PIB形成。目标4需要对新基因进行遗传筛选：一种获得功能 筛选以确定影响中央幼虫大脑间质分支的基因， 筛选以鉴定在特定谱系中表达的基因/增强子。

connectivity in the brain. In this grant we will address the question of neurite branching in Drosophila. Neurite branching is one of the key processes that shape connectivity in the CNS of all animals. Understanding the molecular mechanisms of neurite branching will be important, not only for the neuroscientist interested in understanding brain development, but also for the clinician following the rapidly evolving therapeutic approaches that utilize transplants of undifferentiated neurons for neurodegenerative diseases, such as Parkinson's or Alzheimer's disease. For such transplants to be effective, it would greatly help if one could manipulate the manner in which the donor neurons interact with the host's microenvironment and, in response, form branched neurites that become integrated within the host's circuitry. Drosophila provides an excellent model system to address neurite branching at a high level of resolution because the wealth of molecular-genetic tools and the fact that neurons of the brain fall into lineages that are generated from a relatively small number of stem cell-like neuroblasts. In work of the previous funding period we have generated a comprehesive map of the larval brain lineages and their initial path of projections in the larva. The nerve fiber tracts of each lineage undergo a characteristic pattern of branching, which makes it possible to recognize and work with them. The proposed studies address the following hypotheses: (i) interaction between axons and glia at the cortex-neuropile boundary set branchpoints; (ii) within axons, the setting of branchpoints depends on the Par complex, which according to (now extended) preliminary results is localized at future branchpoints; (iii) the interaction between neurites and glia and the ensuing concentration of Par3 at the branchpoint involves cadherin-mediated interaction. Our main support for this set of hypotheses is the observation that reducing each of the three factors, glia, Par, and DEcadherin results in a similar phenotype in larval lineages, which consists in defects in proximal branching. In aim #1 we will investigate structurally and experimentally neurite-glia interactions. In aims #2 and #3 we propose an experimental and genetic analysis of two molecular pathways, the Par complex and the Cadherin adhesion complex, in PIB formation. Aim#4 entails genetic screens for novel genes: a gain-offunction screen to identify genes that affect interstitial branching in the central larval brain, and a second screen to identify genes/enhancers expressed in specific lineages.