Regulation of Development by LRP4 at Drosophila Peripheral Synapses

项目摘要 神经系统是一个极其复杂的网络，它通过错综复杂和严密的调控而发展。 流程。神经发育的一个关键方面是神经元之间的连接的形成。突触 通过一系列复杂的步骤形成它们，以确保它们在生物体的整个生命周期中具有持久的功能。 这些步骤的调节对于正确的突触组织是必不可少的，但分子机制 这些事件背后的原因仍然不完全清楚。对这些过程的了解对于 了解突触发育过程中发生的细胞事件，以及可能 神经发育障碍，包括自闭症。这款F31 Ruth L.Kirchstein NRSA的目标是 来解决有关突触发育的基本问题。 这一建议旨在通过研究细胞表面来阐明突触发育的一种新机制 受体LRP4。该蛋白在发育中的哺乳动物神经肌肉接头(NMJ)中具有明确的作用， 但最近在其他具有更神秘功能的突触上发现了这种现象。在哺乳动物的NMJ，LRP4 与阿格林和马斯克一起发挥突触后的作用。在其他突触上，包括果蝇 CNS，LRP4已经被发现是突触前的，并且不依赖于Agin和Musk。初步数据显示， 果蝇幼虫NMJ也表明在突触发育中起重要作用。这个突触提供了一个 提供了剖析LRP4在突触发育过程中发挥作用的新机制的机会 分子遗传学工具的可用性和单一突触解析的可实现性。 果蝇NMJ中由LRP4控制的细胞事件将使用高分辨率成像进行评估， 遗传学和生物化学。表达研究将告知LRP4是在突触前还是在 突触后促进发展。功能丧失表型的分析将决定发育 由这些感兴趣的基因调控的过程。遗传和生化方法将避开这条途径。 以此来规范这些过程。总体而言，这些研究将为新角色提供独特的见解 LRP4在调节突触发育中的作用。这个项目将使人们对基础知识的理解 发展机制，并提供对神经发育障碍的见解。

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.