Mechanisms of scaling growth in Drosophila neuromuscular junction development

总结 器官、细胞和亚细胞结构的生长在发育过程中必须协调， 产生一个比例和功能有机体。然而，控制规模增长的机制 亚细胞水平还不清楚。这个过程在神经系统中尤其重要， 其中突触大小与目标大小的不正确匹配可导致神经发育障碍。这 一项提案将使用果蝇神经肌肉突触，这种突触在幼虫时期经历了广泛的生长， 发展，作为一个模型系统，以了解规模增长。增加或减小 胰岛素受体信号通路中的细胞自主性变化导致靶肌肉成比例地 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 单个肌肉的大小会特别影响该肌肉上的突触，这意味着局部信号 不依赖于循环激素或发育时间变化的机制。的首要目标 该建议是识别将肌肉生长状态传达给运动神经元末梢的信号。 比较胰岛素受体途径不同组分的作用， 膜脂磷脂酰肌醇（3，4，5）-三磷酸和蛋白质介导的贡献 激酶Akt。将评估磷脂酰肌醇（3，4，5）-三磷酸的候选效应物在以下方面的作用： 规模化生长，遗传筛选将用于识别跨膜或分泌分子参与 发送一个或两个信号。第二个目标将使用实时成像来更好地描述该过程 并将其与神经元活动诱导的生长进行比较。这些 实验将区分新的终扣的增加是否需要肌肉突触的局部积累， 成分，或者肌肉是否提供了一个更弥散的信号，增加了发生终断的可能性。 阵阐明发育生长从突触后传递的机制 对突触前细胞的研究可能有助于了解自闭症和精神分裂症等疾病， 提供了一个更基本的框架来理解一般的规模增长。

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.