Mechanisms of scaling growth in Drosophila neuromuscular junction development

摘要 器官、细胞和亚细胞结构的生长在发育过程中必须协调，以 生产出一个比例适中、功能齐全的有机体。然而，控制规模增长的机制 亚细胞水平还没有被很好地理解。这一过程在神经系统中尤为重要， 突触大小与靶大小的不正确匹配可能会导致神经发育障碍。这 提案将使用果蝇的神经肌肉突触，这种突触在幼虫期间经历广泛的生长 发展，作为理解规模增长的模型系统。增加或减小 靶肌肉受细胞自主胰岛素受体信号通路变化的影响成正比 突触大小的变化，保持突触大小与肌肉大小的恒定比例。改变 单个肌肉的大小特别影响该肌肉上的突触，这意味着局部信号 这种机制不依赖于循环荷尔蒙或发育时机的改变。的第一个目标 这项提议是为了识别将肌肉生长状态传达给运动神经元终末的信号。 比较不同成分的胰岛素受体通路的作用发现不同的 膜脂磷脂酰肌醇(3，4，5)-三磷酸和蛋白质的作用 激活剂Akt.将评估磷脂酰肌醇(3，4，5)-三磷酸的候选效应物在 按比例生长，基因筛查将被用来识别涉及的跨膜或分泌分子 在传输一个或两个信号时。第二个目标将使用实时成像来更好地描述这一过程 并将其与神经元活动诱导的生长进行比较。这些 实验将区分新突起的增加是否需要肌肉突触的局部积累 肌肉是否提供了更弥漫的信号，从而增加了比赛的可能性 队形。阐明发育生长从突触后传递的机制 突触前细胞可能提供对自闭症和精神分裂症等疾病的洞察，除了 提供了一个更基本的框架，以便从总体上理解规模增长。

Summary The growth of organs, cells and subcellular structures must be coordinated during development to produce a proportional and functional organism. However, the mechanisms that control scaling growth at the subcellular level are not well understood. This process is especially important in the nervous system, where incorrect matching of synapse size to target size can result in neurodevelopmental disorders. This proposal will use Drosophila neuromuscular synapses, which undergo extensive growth during larval development, as a model system to understand scaling growth. Increasing or decreasing the size of the target muscle by cell-autonomous changes in the Insulin Receptor signaling pathway results in proportional changes in the size of the synapse, maintaining a constant ratio of synapse size to muscle size. Altering the size of a single muscle specifically affects the synapses on that muscle, implying a local signaling mechanism that does not rely on circulating hormones or changes in developmental timing. The first aim of this proposal is to identify signals that communicate muscle growth status to motor neuron terminals. Comparing the effects of different components of the Insulin Receptor pathway revealed separate contributions mediated by the membrane lipid phosphatidylinositol (3,4,5)-triphosphate and the protein kinase Akt. Candidate effectors of phosphatidylinositol (3,4,5)-triphosphate will be evaluated for their role in scaling growth, and a genetic screen will be used to identify transmembrane or secreted molecules involved in transmitting one or both signals. The second aim will use live imaging to better characterize the process of developmental synapse growth and compare it to growth induced by neuronal activity. These experiments will distinguish whether addition of new boutons requires local accumulation of muscle synaptic components, or whether the muscle provides a more diffuse signal that increases the probability of bouton formation. Elucidating the mechanism by which developmental growth is communicated from postsynaptic to presynaptic cells may provide insight into disorders such as autism and schizophrenia, in addition to providing a more basic framework to understand scaling growth in general.