Regulation of Development by LRP4 at Drosophila Peripheral Synapses

项目摘要 神经系统是一个非常复杂的网络，通过复杂和严格的监管发展 流程.神经发育的一个关键方面是神经元之间连接的形成。突触 通过一系列复杂的步骤来形成，以确保它们在生物体的整个生命中的持久功能。 这些步骤的调节对于正确的突触组织是必不可少的，但是 这些事件背后的原因仍然不完全清楚。对这些过程的了解是 了解突触发育过程中发生的细胞事件，以及可能 在神经发育障碍中受损，包括自闭症。这款F31 Ruth L. Kirchstein NRSA是 来解决突触发育的基本问题。 该建议旨在通过研究细胞表面来阐明突触发育的新机制 受体LRP 4。这种蛋白质在发育中的哺乳动物神经肌肉接头（NMJ）中具有明确的作用， 但最近在其他突触中也发现了，其功能更神秘。在哺乳动物NMJ，LRP 4 与聚集蛋白和MuSK一起在突触后起作用。在其他突触上，包括果蝇 CNS中LRP 4在突触前被发现，并且独立于Agrin和MuSK。初步数据 果蝇幼虫的NMJ也表明在突触发育中的重要作用。这个突触提供了一个 有机会解剖LRP 4在突触发育过程中发挥作用的新机制， 分子遗传学工具的可用性和单个突触分辨率的可重复性。 将使用高分辨率成像来评估果蝇NMJ中由LRP 4控制的细胞事件， 遗传学和生物化学。表达研究将告知LRP 4是否在突触前发挥作用， 突触后促进发育。功能表型丧失的分析将确定发育 由这些感兴趣的基因调控的过程。遗传学和生物化学的方法将回避这一途径 这些过程都是由它来控制的。总的来说，这些研究将提供独特的见解， LRP 4在调节突触发育中的作用该项目将告知基本的理解 发育机制，并提供深入了解神经发育障碍。

Project Summary The nervous system is a vastly complex network which develops through intricate and tightly regulated processes. One critical aspect of neurodevelopment is the formation of connections between neurons. Synapses form through a series of complex steps to ensure their lasting functionality throughout the life of an organism. The regulation of these steps is essential for proper synaptic organization, but the molecular mechanisms that underlie these events remain incompletely understood. Knowledge of these processes is central to the understanding of cellular events that occur during synaptic development, as well as the mechanisms which may be impaired in neurodevelopmental disorders, including autism. The goal of this F31 Ruth L. Kirchstein NRSA is to address fundamental questions about synaptic development. This proposal aims to elucidate a novel mechanism of synaptic development by investigating the cell surface receptor LRP4. This protein has a well-defined role at the developing mammalian neuromuscular junction (NMJ), but has recently been found at other synapses, with more enigmatic functions. At the mammalian NMJ, LRP4 functions postsynaptically in conjunction with Agrin and MuSK. At other synapses, including in the Drosophila CNS, LRP4 has been found presynaptically and independent of Agrin and MuSK. Preliminary data at the Drosophila larval NMJ also indicates an important role in synaptic development. This synapse provides an opportunity for dissection of a novel mechanism by which LRP4 functions during synaptic development, given the availability of molecular genetics tools and achievability of single synapse resolution. The cellular events governed by LRP4 at the Drosophila NMJ will be assessed using high resolution imaging, genetics, and biochemistry. Expression studies will inform whether LRP4 functions at the presynapse or postsynapse to promote development. Analysis of loss of function phenotypes will determine the developmental processes regulated by these genes of interest. Genetic and biochemical approaches will eludicate the pathway by which these processes are regulated. Overall, these studies will provide unique insights into a novel role for LRP4 in regulating synaptic development. This project will inform the understanding of fundamental developmental mechanisms, and provide insights into neurodevelopmental disorders.