Regulation of synaptic targeting in the Drosophila larval neuromuscular system by immunoglobulin superfamily cell surface proteins

免疫球蛋白超家族细胞表面蛋白对果蝇幼虫神经肌肉系统突触靶向的调节

• 批准号: 10011886
• 负责人: KAI G ZINN
• 金额: $ 35.94万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011886
• 关键词: Axon; Binding; Biological Models; Birth; Brain; Brain Diseases; Cell Communication; Cell Surface Proteins; Cells; Code; Complex; Development; Disease; Drosophila genus; Extracellular Domain; Family; Fetal Development; Fishes; Genes; Genetic; Goals; Health; Human; Immunoglobulins; In Vitro; Individual; Insecta; Label; Lead; Logic; Mammals; Mediating; Motor; Motor Neurons; Muscle; Muscle Fibers; Mutation; Nervous system structure; Neuraxis; Neurons; Optic Lobe; Orthologous Gene; Outcome; Pathway interactions; Pattern; Property; Proteins; Pupa; Regulation; Research; Research Project Grants; Signal Transduction; Specificity; Surface; Synapses; System; Tertiary Protein Structure; Time; Ursidae Family; Work; axon guidance; experimental study; extracellular; in vivo; insight; nerve supply; nervous system development; neural circuit; neurodevelopment; neuromuscular system; neuronal circuitry; novel strategies; presynaptic; programs; receptor; selective expression; superior colliculus Corpora quadrigemina; synaptogenesis; tool

PROJECT SUMMARY/ABSTRACT Many cell surface proteins (CSPs) that are essential for neural development have been identified, but we still lack an overall understanding of the logic of the cell-cell interactions that program the assembly of neural circuits. Our long-term goal is to understand how cell-cell interactions mediated by CSPs program the assembly of the intricate synaptic patterns of nervous systems. Many years ago, it was proposed that in “hard- wired” systems such as the fish optic tectum and the insect CNS and neuromuscular system, each neuron or neuronal type is labeled by “identification tags” that control synaptic specificity, and that these tags are represented by specific CSPs called “surface labels”. The original hypotheses predicted that surface labels that control synaptic specificity should be: 1) expressed on small subsets of neurons or muscles, 2) recognized by receptors whose expression is also restricted to small subsets of neurons (and might themselves be surface labels), 3) required for or influence the formation of specific synaptic connections, 4) encoded by families of related genes. We discovered a network of interacting CSPs that satisfies all of these criteria, using a new approach in which we selected proteins for in vivo analysis from a global in vitro interaction network. The Garcia group at Stanford and our group at Caltech generated an extracellular “interactome” for all Drosophila immunoglobulin superfamily (IgSF) proteins, and found a subfamily of 21 2-Ig domain cell-surface proteins, the Dprs, that selectively binds to another subfamily of 9 3-Ig domain proteins, the DIPs. Each dpr and DIP gene is expressed by a small and unique subset of neurons, and mutations in these genes produce specific alterations in synaptic connectivity. The objectives of the present application are to define whether and how interactions between Dprs and DIPs constitute a “connectivity code” that contributes to wiring specificity in the Drosophila larval neuromuscular system. The primary hypothesis underlying this application is that engagement of Dprs with their DIP partners provides information that can control synaptic targeting decisions. We plan to attain the objectives of this application through three specific aims. The first of these examines how Dpr-DIP interactions control formation of an axon branch of a specific motor neuron. The second analyzes how another DIP expressed on a single motor neuron controls innervation of its muscle target. The third creates tools for analysis of all Dprs and DIPs and identifies those expressed by specific motor neurons and muscles. The expected outcome of the proposed research will be the acquisition of new insights into the mechanisms by which interactions among CSPs control the specification of synaptic connections in a relatively simple model system. This will have a significant positive impact for human health by increasing our understanding of conserved mechanisms involved in nervous system development and disease in humans.

项目概要/摘要 许多对神经发育至关重要的细胞表面蛋白（CSP）已被鉴定，但我们仍然 缺乏对细胞间相互作用逻辑的全面理解，这些相互作用对神经细胞的组装进行编程 电路。我们的长期目标是了解 CSP 介导的细胞间相互作用如何编程 神经系统复杂的突触模式的组装。很多年前，就有人提出“硬 有线”系统，例如鱼的视顶盖和昆虫的中枢神经系统和神经肌肉系统，每个神经元或 神经元类型由控制突触特异性的“识别标签”来标记，并且这些标签是 由称为“表面标签”的特定 CSP 表示。最初的假设预测表面标签 控制突触特异性应该是：1）在神经元或肌肉的小子集上表达，2）被 其表达也仅限于一小部分神经元的受体（并且本身可能是表面的） 标签），3）需要或影响特定突触连接的形成，4）由家族编码 相关基因。我们使用一种新的方法发现了一个满足所有这些标准的交互 CSP 网络 我们从全球体外相互作用网络中选择蛋白质进行体内分析。这 斯坦福大学的加西亚小组和加州理工学院的我们小组为所有果蝇生成了细胞外“相互作用组” 免疫球蛋白超家族 (IgSF) 蛋白，并发现了 21 个 2-Ig 结构域细胞表面蛋白的亚家族，即 Dprs，选择性结合 9 个 3-Ig 结构域蛋白的另一个亚家族，即 DIP。每个 dpr 和 DIP 基因是 由一小部分独特的神经元表达，这些基因的突变会产生特定的改变 在突触连接中。本申请的目的是定义是否以及如何交互 Dprs 和 DIPs 之间构成了一个“连接代码”，有助于果蝇的接线特异性 幼虫的神经肌肉系统。该应用程序的主要假设是 Dprs 的参与 与他们的 DIP 合作伙伴一起提供可以控制突触目标决策的信息。我们计划达到 该应用程序通过三个具体目标实现目标。第一个检查 Dpr-DIP 相互作用如何 控制特定运动神经元轴突分支的形成。第二个分析另一个DIP如何 在单个运动神经元上表达的控制其肌肉目标的神经支配。第三个创建工具 分析所有 Dpr 和 DIP，并识别由特定运动神经元和肌肉表达的那些。 拟议研究的预期结果将是通过以下方式获得对该机制的新见解： CSP 之间的相互作用在相对简单的模型中控制突触连接的规范 系统。这将通过增加我们对人类健康的了解而产生重大的积极影响。 涉及人类神经系统发育和疾病的保守机制。