IgSF protein interactions drive specificity in circuit wiring and synaptic elaboration

IgSF 蛋白质相互作用驱动电路布线和突触精细化的特异性

• 批准号: 10631084
• 负责人: Robert Arnulfo Carrillo
• 金额: $ 39.95万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631084
• 关键词: Address; Affect; Affinity; Automobile Driving; Axon; Binding; Binding Proteins; Cell Communication; Cell Surface Proteins; Cells; Clinical; Code; Collaborations; Complex; Cues; Data; Development; Developmental Process; Disease; Drosophila genus; Dyslexia; Family; Foundations; Genes; Genetic; Goals; Growth; Homo; Human; Immunoglobulins; Individual; Link; Maps; Mediating; Modeling; Molecular; Morphology; Motor Activity; Motor Neurons; Multigene Family; Muscle; Nervous System; Neurobiology; Neurons; Pathway interactions; Pattern; Play; Positioning Attribute; Presynaptic Terminals; Process; Property; Proteins; Reagent; Regulation; Research; Resolution; Role; Schizophrenia; Shapes; Signal Pathway; Signal Transduction; Specific qualifier value; Specificity; Stereotyping; Structure; Synapses; Testing; Variant; Visual; Work; autism spectrum disorder; axon guidance; combinatorial; genetic approach; genetic manipulation; insight; member; mutant; nervous system disorder; neural; neural circuit; neuromuscular; neuromuscular system; novel; postsynaptic; presynaptic; programs; synaptic function; synaptogenesis

Project Summary In this application, we examine the molecular mechanisms that instruct neural wiring and axon terminal elaboration. We focus on the Drosophila neuromuscular system due to its invariant connectivity, limited synaptic partners, and accessibility. Given that this ‘simple’ circuit has been studied for over four decades, it is somewhat surprising that fundamental questions still exist as to how motor neurons choose their appropriate muscle targets and how each motor neuron develops a unique, yet stereotyped, axon terminal structure that underlies synaptic function. Conceptually, both of these developmental processes rely on specificity cues to guide synaptic partner matching (role 1) and synaptic elaboration at each axon terminal (role 2). In support of the first role, we previously discovered two interacting cell surface proteins (CSPs), DIP-α and Dpr10, that are required for wiring a motor neuron to a subset of muscles. In support of the second role, these CSPs continue to be expressed after connectivity, implying additional functions in synaptic development. Our central hypothesis is that combinatorial Dpr-DIP interactions, in addition to specifying synaptic connections, also participate in determining the structure and function of specified synapses. Insights into circuit development arose in a prior collaboration where we characterized the ‘Dpr-ome’, the set of interactions between two families of the immunoglobulin superfamily, the Dprs and DIPs. These 32 proteins bind to one another in unique combinations, and our preliminary data reveal unique expression patterns in the Drosophila larval neuromuscular circuit. Additionally, our data support a combinatorial Dpr-DIP interaction model that leverages cis/trans interactions to instruct highly specific synaptic partnerships. We also reveal a novel signaling pathway that underlies local synaptic elaboration. Given our findings and genetic reagents, we are in a unique position not only to compare axon branch-specific identification tags but also to ask if synaptic elaboration of neighboring axon terminals can be independently regulated. In the first aim, we capitalize on the Dpr-ome and the expression of 6 DIPs in multi-innervating motor neurons to perform single-cell genetic manipulations and examine how combinatorial Dpr-DIP codes instruct connectivity. In addition, we generate affinity variants to reveal a coordinated cis/trans interaction model that enhances specificity. In the second aim, we utilize functional and genetic approaches to understand how co-innervating inputs develop unique morphological and functional properties. We identify a novel crosstalk signaling pathway between axon arbors that locally sculpts NMJ size. Overall, these studies will uncover fundamental developmental programs required for neural circuit wiring and axon terminal elaboration, with emphasis on how CSP codes modulate each of these processes.

项目摘要 在此应用中，我们检查了指导神经接线和轴突末端的分子机制 阐述。 突触合作伙伴和可访问性。 令人惊讶的是，基本问题仍然存在于运动神经元选择其合适的问题 肌肉靶标以及每个电动机神经元如何形成独特但刻板的轴突末端结构， 概念上的突触功能，这两个发展过程都依赖于特异性提示 引导突触伴侣匹配（角色1）和每个轴突终端的突触阐述（角色2） 第一个角色是我们以前发现了两个相互作用的细胞表面蛋白（CSP），DIP-α和DPR10，它们是 将电动神经元接线至肌肉子集所需。 在连接后表示，这意味着我们的中心中的其他功能 假设是，除了指定突触连接外，组合DPR-DPR相互作用 参与确定指定突触的结构和功能。 在先前的合作中出现，我们表征了“ dpr-ome”，这是两个之间的相互作用集 免疫球蛋白超家族的家族，dprs和32个蛋白质。 独特的组合和我们的预启示数据Revela Revelal唯一的表达模式在果蝇幼虫中 神经肌肉电路。 顺式/反式互动指导高度特定的突触伙伴关系。 鉴于我们的发现和遗传试剂，这是局部突触阐述。 不仅要比较轴突分支特异性标签，而且要询问突触阐述是否关闭 相邻的轴突终端可以在第一个目标中进行调节。 在多发运动神经元中进行6次倾斜以执行单细胞基因操纵和 检查组合DPR-DIP代码如何指示连接性。 揭示一个协调的顺式/反式相互作用模型，以增强特异性。 功能和遗传方法了解共同发动的投入如何发展开发出独特的形态和 功能性能。 NMJ的大小。 接线和轴突终端详细说明，重点是代码如何调节这些过程中的每个过程。