Regulation of synaptic growth and plasticity in Drosophila

描述(由申请人提供)： 对突触生长的适当调节是神经回路形成和可塑性的基础。突触发育和可塑性缺陷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行性变。然而，调控这些过程的分子机制仍然不完全清楚。使用果蝇幼虫NMJ作为实验模型来研究这些过程，我对神经残骸(NWK)进行了详细的表征，神经残骸(NWK)是突触生长的关键负调控因子，同时，通过识别突触正常生长所需的其他基因来扩大我的研究范围，NWK编码一种神经元特异性SH3结构域蛋白，与黄蜂一起发挥作用。值得注意的是，一名人类NWK家庭成员被牵连到一种严重的精神发育迟滞。我已经确定了NWK在突触BMP生长信号的内吞调节中的作用。具体地说，我发现NWK在功能上和物理上与内吞机制的组件相互作用，包括Dynamin和Dap160/Intersectin，并通过与BMP受体Thickvines的物理相互作用负向调节BMP逆行生长信号。NWK中突触的过度生长对BMP信号水平敏感，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，在NWK突变体中，下游效应分子磷酸化的MAD水平显著增加，而在过度表达NWK的运动神经元中则降低，这直接表明了NWK下调BMP信号的能力。这项建议的目的是揭示NWK调节突触BMP信号的分子机制(Aim1)，并通过表征My Genetic Screens(AIM2)中发现的一种新的突触生长调节因子来更全面地了解突触生长控制。公共卫生相关性：由于突触生长调节对正常神经功能和行为的核心重要性，并且由于调节突触发育和可塑性的分子机制很可能是保守的，阐明NWK和其他新基因在果蝇突触生长调节中的作用将为人类神经疾病中可能受损的机制提供重要的见解，并确定潜在的治疗干预靶点。

DESCRIPTION (provided by applicant): 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 (Aim1), and to obtain a more complete understanding of synaptic growth control by characterizing a novel synaptic growth regulator identified in my genetic screens (Aim2). PUBLIC HEALTH RELEVANCE: 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.