Regulation of synaptic growth and plasticity in Drosophila

描述（由申请人提供）： 突触生长的适当调节是神经回路形成和可塑性的基础。突触发育和可塑性的缺陷与广泛的神经系统疾病相关，包括精神发育迟滞、运动、认知和心理障碍以及神经变性。然而，调节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，我已经进行了详细的表征神经残骸（Nwk），突触生长的一个关键的负调节器，同时，在平行的，扩大我的调查，通过识别额外的基因所需的突触的正确生长，Nwk编码神经元特异性SH 3结构域蛋白，与黄蜂的功能。值得注意的是，人类Nwk家族成员与严重形式的精神发育迟滞有关。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，并通过与BMP受体Thickveins的物理相互作用负调节BMP逆行生长信号。nwk中的突触过度生长对BMP信号传导的水平敏感，并且nwk的丢失促进BMP诱导的突触过度生长。相反，Nwk的过表达抑制BMP诱导的突触过度生长。此外，下游效应物磷酸化MAD的水平在nwk突变体中显著增加，而在过表达Nwk的运动神经元中降低，直接证明了Nwk下调BMP信号传导的能力。该提案的目标是揭示Nwk调节突触BMP信号传导的分子机制（Aim 1），并通过表征在我的遗传筛选中鉴定的新型突触生长调节剂（Aim 2）来获得对突触生长控制的更完整的理解。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，并且由于介导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，将为人类神经系统疾病中可能受损的机制提供重要的见解，并确定治疗的潜在靶点。干预

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.