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.

项目概要 神经系统是一个极其复杂的网络，通过复杂且严格的调控而发展 流程。神经发育的一个关键方面是神经元之间连接的形成。突触 通过一系列复杂的步骤形成，以确保其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至关重要，但其分子机制 这些事件的背后原因仍不完全清楚。了解这些过程对于 了解突触发育过程中发生的细胞事件以及可能的机制 神经发育障碍（包括自闭症）会受到损害。 F31 Ruth L. Kirchstein NRSA 的目标是 解决有关突触发育的基本问题。 该提案旨在通过研究细胞表面来阐明突触发育的新机制 受体LRP4。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发现了更多神秘的功能。在哺乳动物 NMJ，LRP4 与 Agrin 和 MuSK 一起在突触后发挥作用。在其他突触，包括果蝇 中枢神经系统 (CNS) 已发现 LRP4 位于突触前且独立于 Agrin 和 MuSK。初步数据位于 果蝇幼虫 NMJ 也表明在突触发育中发挥着重要作用。该突触提供了 鉴于 LRP4 在突触发育过程中发挥作用的新机制，有机会进行剖析 分子遗传学工具的可用性和单个突触分辨率的可实现性。 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 是否在突触前或 突触后促进发育。功能丧失表型的分析将决定发育 由这些感兴趣的基因调节的过程。遗传和生化方法将阐明这一途径 这些过程受其监管。总的来说，这些研究将为新角色提供独特的见解 LRP4 调节突触发育。该项目将帮助人们了解基本知识 发育机制，并提供对神经发育障碍的见解。