Regulation of synaptic growth and plasticity in Drosophila

对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 突触的发育和可塑性与一系列神经疾病有关，包括 智力低下、运动、认知和心理障碍，以及神经退化。然而， 调控这些过程的分子机制仍不完全清楚。利用果蝇 以NMJ幼虫为实验模型，对这些过程进行了详细的研究 神经残骸(NWK)，突触生长的关键负调控因子的特征，同时，平行地， 通过鉴定正常生长所需的其他基因来扩大我的研究范围 突触，NWK编码一种神经元特异性SH3结构域蛋白，与Wasp一起发挥作用。值得注意的是， 人类NWK家族成员被牵连成一种严重的精神发育迟滞。我已经确定了一个 NWK在突触BMP生长信号的细胞内调节中的作用。具体地说，我发现NWK 与内吞机械的组件在功能和物理上相互作用，包括动力素和 Dap160/Intersectin通过物理相互作用负向调节BMP逆行生长信号 与骨形态发生蛋白受体的粗大血管有关。NWK中突触过度生长对BMP信号和 NWK的缺失促进了BMP诱导的突触过度生长。相反，NWK的过度表达抑制了 BMP诱导的突触过度生长。此外，下游效应器磷酸化MAD的水平是 在NWK突变体中显著增加，而在过度表达NWK的运动神经元中显著减少 展示了NWK下调BMP信号的能力。这项提案的目标是揭示 NWK调节突触BMP信号的分子机制(目标1)，并获得更多 通过描述一种新的突触生长调节因子来完全理解突触生长控制 在我的基因屏幕上识别(目标2)。因为突触生长调节对 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 在果蝇的突触生长调节中，应该为可能的机制提供重要的见解 在人类神经疾病中受到损害，并确定潜在的治疗干预目标。

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.