Regulation of Development by LRP4 at Drosophila Peripheral Synapses

LRP4 对果蝇外周突触发育的调节

• 批准号: 10326371
• 负责人: Alison DePew
• 金额: $ 4.68万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326371
• 关键词: Address; Affect; Agrin; Autoantibodies; Biochemical; Biochemistry; Biological; Biological Assay; Biological Models; Cell Surface Receptors; Cells; Complex; Cytoskeleton; Data; Defect; Development; Developmental Process; Disease; Dissection; Drosophila genus; Electron Microscopy; Ensure; Etiology; Event; Failure; Genes; Genetic; Glutamate Receptor; Goals; Growth; Immunohistochemistry; Impairment; Intellectual functioning disability; Knowledge; Lead; Life; Mechanics; Mediating; Microscopic; Microscopy; Molecular; Molecular Genetics; Motor Neurons; Muscle; Myasthenia Gravis; National Research Service Awards; Nervous System Physiology; Nervous system structure; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuromuscular Junction; Neurons; Organism; Pathway interactions; Peripheral; Phenotype; Phosphotransferases; Presynaptic Receptors; Process; Protein Kinase; Proteins; Regulation; Resolution; Role; Series; Signal Transduction; Signaling Molecule; Synapses; System; Tissues; Work; autism spectrum disorder; confocal imaging; density; experimental study; grasp; high resolution imaging; imaging genetics; improved; insight; interest; loss of function; mutant; nervous system development; neurodevelopment; novel; overexpression; patient population; postsynaptic; presynaptic; receptor; recruit; synaptic function; synaptogenesis; tool

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.

项目摘要 神经系统是一个非常复杂的网络，它通过复杂且严格的调节而发展 过程。神经发育的一个关键方面是神经元之间联系的形成。突触 通过一系列复杂的步骤形成，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适当的突触组织至关重要，但是分子机制 这些事件的基础尚未完全理解。对这些过程的了解至关重要 了解突触发育过程中发生的细胞事件，以及可能的机制 在包括自闭症在内的神经发育障碍中受到损害。这个F31 Ruth L. Kirchstein Nrsa的目标是 解决有关突触发展的基本问题。 该建议旨在通过研究细胞表面来阐明一种新型突触发育机制 受体LRP4。该蛋白质在发育中的哺乳动物神经肌肉连接（NMJ）中具有明确的作用。 但是最近在其他突触中发现了更神秘的功能。在哺乳动物NMJ，LRP4 与Agrin和Musk结合后突触的功能。在其他突触，包括果蝇中 CNS，LRP4被发现是突触前的，独立于Agrin和Musk。初步数据 果蝇幼虫NMJ还表明在突触发育中起重要作用。这个突触提供了 鉴于LRP4在突触发育过程中发挥作用的新机制的解剖机会 分子遗传学工具的可用性以及单个突触分辨率的可用性。 由LRP4在果蝇NMJ处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在促进前还是在 促进发展后的发展。分析功能表型的丧失将决定发展 这些感兴趣基因调节的过程。遗传和生化方法将避免途径 这些过程受到调节。总体而言，这些研究将为您提供对新作用的独特见解 LRP4在调节突触发育方面。该项目将告知人们对基本的理解 发育机制，并提供有关神经发育障碍的见解。