Mechanisms and functions of Drosophila motoneuron dendritic shape development

描述（由申请方提供）：所有动物的脑均由具有细胞类型特异性形态的单个神经元组成。神经元的显着不同的树枝状结构决定了神经回路的两个基本方面：首先，它决定了哪些突触前神经元可以接触突触后树枝状结构。第二，影响突触后树突对突触输入的总和和计算。因此，健康的脑功能依赖于树突结构的正确发育，树突结构缺陷与许多神经退行性疾病有关，如Rett-和脆性-X综合征。识别调节树突结构发育和树突状乔木上突触放置的分子机制对于理解健康和患病大脑中的神经回路发育至关重要。尽管最近成功地确定了关键的分子机制调节树突乔木的发展，我们的知识树突结构的功能后果的错误调节突触伴侣匹配和突触输入处理在突触后神经元仍然零碎。 这项研究的目的是解开树突状结构发展的具体方面的分子机制，以及假调节的功能后果。在发育过程中，树突状结构受先天遗传因素、引导线索、体液线索和神经元活动的调节。尽管这些信号中的一些可能通过类似的细胞内信号传导途径整合，但不同的信号可以独立地影响同一神经元中的各种树突特征，例如树突分支长度和数量、树突区域边界以及树突乔木在其区域内的正确间距。在最近几年，基本的新见解的分子机制，控制树突的自我回避和平铺，从而正确的树突乔木间距，来自果蝇遗传模型系统。然而，在中枢神经系统的电路组装过程中，这些机制如何与突触伴侣匹配相互作用仍然很不清楚。因此，拟进行的实验将测试果蝇运动神经元树突发育过程中树突的自我回避机制与中枢突触形成的相互作用。控制运动神经元树突状结构特征的定量数据库将作为基石，有针对性的遗传操作，测试介导树突状排斥的关键分子的作用。此外，我们已经确定了感觉神经元，突触到这些运动神经元，允许测试树突状乔木生长过程中的树突排斥和突触伴侣匹配之间的功能相互作用。此外，正确和错误的树突状结构的调节将与神经元功能的计算方法和电生理记录在控制和遗传操作的动物。我们期望获得新的见解，在发展过程中的树突乔木结构的调节，以及在成熟神经元的树突乔木缺陷的功能后果。

DESCRIPTION (provided by applicant): The brains of all animals are composed out of individual neurons with cell type specific morphologies. The remarkably diverse dendritic architecture of neurons determines two fundamental aspects of neural circuitry: First, it dictates which presynaptic neurons can contact the postsynaptic dendritic arbor. Second, it affects the summation and computation of synaptic input in the postsynaptic dendritic arbor. Consequently, healthy brain function relies on the correct development of dendritic structure, and dendritic architecture defects have been associated with a number of neurodegenerative diseases, such as Rett- and Fragile-X Syndrome. Identifying the molecular mechanisms that regulate dendritic architecture development and synapse placement on dendritic arbors is imperative to understanding neural circuit development in the healthy and in the diseased brain. Despite recent success in identifying key molecular mechanisms regulating dendritic arbor development, our knowledge on the functional consequences of dendritic architecture mis-regulation for synaptic partner matching and for synaptic input processing in the postsynaptic neuron remains fragmentary. This study aims to unravel molecular mechanisms underlying specific aspects of dendritic architecture development as well as the functional consequences of false regulation. During development dendritic structure is regulated by innate genetic factors, guidance cues, humoral cues, and by neuronal activity. Although some of these signals may be integrated by similar intracellular signaling pathways, different signals can independently affect various dendritic features in the same neuron, such as dendritic branch lengths and numbers, dendritic territory borders, and the correct spacing of dendritic arbors within their territories. During recent years, fundamental new insights into the molecular mechanisms that control dendritic self-avoidance and tiling, and thereby correct dendritic arbor spacing, have come from the Drosophila genetic model system. However, it remains largely unclear how these mechanisms interact with synaptic partner matching during circuit assembly in the central nervous system. Therefore, the proposed experiments will test how dendritic self-avoidance mechanisms interact with central synapse formation during dendritic arbor development of Drosophila motoneurons. A quantitative database on control motoneuron dendritic architecture features will serve as bedrock for testing the roles of key molecules mediating dendritic repulsion by targeted genetic manipulation. In addition, we have identified sensory neurons that synapse onto these motoneurons, allowing one to test for functional interactions between dendritic repulsion and synaptic partner matching during dendritic arbor growth. Furthermore, correct and false dendritic architecture regulation will be related to neuronal function by computational approaches and electrophysiological recordings in control and genetically manipulated animals. We expect to gain novel insight into the regulation of dendritic arbor architecture during development as well as into the functional consequences of dendritic arbor defects in mature neurons.