Regulation of synaptic growth and plasticity in Drosophila

突触生长的适当调节是神经回路形成和可塑性的基础。缺陷 突触发育和可塑性与广泛的神经系统疾病有关， 精神发育迟滞、运动、认知和心理障碍以及神经变性。但 调节这些过程的分子机制仍然不完全清楚。利用果蝇 幼虫NMJ作为一个实验模型来调查这些过程，我进行了详细的 神经损伤（Nwk）的表征，神经损伤是突触生长的关键负调节因子，同时， 通过鉴定正常生长所需的额外基因来扩大我的研究， 突触，nwk编码神经元特异性SH 3结构域蛋白，其与Wasp起作用。值得注意的是，A 人类Nwk-家族成员与严重形式智力迟钝有关。我确定了一个 Nwk在突触处BMP生长信号传导的内吞调节中的作用。具体来说，我发现Nwk 在功能上和物理上与内吞机制的组分相互作用，包括发动蛋白和 Dap 160/Intersectin通过物理相互作用负调控BMP逆向生长信号 与骨形态发生蛋白受体Thickveins结合。nwk中的突触过度生长对BMP信号传导水平敏感， nwk的缺失促进BMP诱导的突触过度生长。相反，Nwk的过表达抑制了 BMP诱导的突触过度生长。此外，下游效应物磷酸化MAD的水平是 显著增加nwk突变体和减少运动神经元过表达Nwk，直接 证明了Nwk下调BMP信号传导的能力。这项提案的目的是揭示 Nwk调节突触BMP信号传导的分子机制（Aim 1），并获得更多 通过描述一种新的突触生长调节剂来全面了解突触生长控制 在我的基因筛选中发现了（目标2）。由于突触生长调节的核心重要性， 正常的神经功能和行为，因为介导突触的分子机制， 发育和可塑性很可能是保守的，阐明了nwk和其他新基因的作用。 在果蝇突触生长调节中的重要作用， 人类神经系统疾病的损害并确定治疗干预的潜在目标。

Proper regulation of synaptic growth is fundamental to the formation and plasticity of neural circuits. Defects in synaptic development and plasticity are associated with a broad range of neurological disorders including mental retardation, motor, cognitive and psychological impairments, and neurodegeneration. However, the molecular mechanisms regulating these processes remain incompletely understood. Using the Drosophila larval NMJ as an experimental model to investigate these processes, I have carried out the detailed characterization of Nervous wreck (Nwk), a key negative regulator of synaptic growth, while, in parallel, expanding my investigations through the identification of additional genes required for the proper growth of synapses, nwk encodes a neuron-specific SH3-domain protein that functions with Wasp. Significantly, a human Nwk-family member has been implicated in a severe form of mental retardation. I have identified a role for Nwk in the endocytic regulation of BMP growth signaling at synapses. Specifically, I found that Nwk interacts functionally and physically with components of the endocytic machinery, including dynamin and Dap160/lntersectin and negatively regulates retrograde BMP growth signaling through a physical interaction with the BMP receptor Thickveins. Synaptic overgrowth in nwk is sensitive to levels of BMP signaling and loss of nwk facilitates BMP-induced synaptic overgrowth. Conversely, overexpression of Nwk suppresses BMP-induced synaptic overgrowth. Moreover, levels of downstream effector phosphorylated MAD are substantially increased in nwk mutants and decreased in motor neurons overexpressing Nwk, directly demonstrating the ability of Nwk to downregulate BMP signaling. The goal of this proposal is to uncover the molecular mechanism by which Nwk regulates BMP signaling at synapses (Aim 1), and to obtain a more complete understanding of synaptic growth control by characterizing a novel synaptic growth regulator identified in my genetic screens (Aim 2). Because of the central importance of synaptic growth regulation to normal neural function and behavior and because the molecular mechanisms that mediate synaptic development and plasticity are very likely to be conserved, elucidating the role of nwk and other novel genes in synaptic growth regulation in Drosophila should provide important insights into mechanisms that may be impaired in human neurological disorders and identify potential targets for therapeutic intervention.