Adherens junction proteins in neuron-glia interactions

神经元-胶质细胞相互作用中的粘附连接蛋白

• 批准号: 9978138
• 负责人: Maxwell Heiman
• 金额: $ 38.72万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978138
• 关键词: Adherens Junction; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Anatomy; Astrocytes; BAIAP1 gene; Binding; Biological Assay; Biology; Brain; Cadherins; Caenorhabditis elegans; Cell physiology; Cell-Matrix Junction; Cells; Data; Defect; Dendrites; Dendritic Spines; Development; Disease; E-Cadherin; Embryo; Epithelial; Epithelial Attachment; Epithelium; Future; Genetic; Genetic Screening; Goals; Human; Image; In Vitro; Individual; Knowledge; Lateral; Lead; Light; Mediating; Microscopy; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Nematoda; Nervous system structure; Neural Cell Adhesion Molecule L1; Neuroglia; Neuron-Glia Cell Adhesion Molecules; Neurons; Nose; Pathway interactions; Process; Proteins; Resolution; Role; Scaffolding Protein; Schizophrenia; Stereotyping; Stroke; Synapses; Syndrome; System; Testing; Tight Junctions; Translating; Traumatic Brain Injury; Work; autism spectrum disorder; experimental study; human disease; in vivo; innovation; knock-down; nervous system disorder; novel; response

ABSTRACT Intercellular interactions between neurons and glia impact diverse neurological diseases, from autism and schizophrenia to amyotrophic lateral sclerosis (ALS) and Alzheimer's disease, as well as responses to stroke and traumatic brain injury. Some of the most important interactions occur at synapses, where the dendritic spines that receive information are attached to astrocytic glia. The molecular mechanisms that assemble these cell-cell attachments remain elusive, owing to the challenges associated with the complexity of the mammalian brain. The goal of this study is to overcome these challenges using an innovative model of dendrite- glia interaction in C. elegans. As described below, the central hypothesis is that dendrite-glia contacts are mediated by proteins from adherens junctions (AJs) in epithelia. Thus, this study lies at the intersection of two fields: applying knowledge of AJs from epithelial biology to a long-standing question in glial biology and, conversely, leveraging the diversity of glial biology to investigate how AJ proteins can be deployed in cellular contexts outside epithelia. In preliminary data, innovative approaches enabled analysis of a novel class of dendrite-glia contact. Two neurons, URX and BAG, extend dendrites to the nose where they intimately wrap a single defined glial cell, the lateral ILso glia. Genetic screens identified factors (SAX-7, GRDN- 1, MAGI-1) that act in glia to anchor these dendrites at the nose during embryonic elongation. When these factors are disrupted, developing dendrites detach from the nose and fail to fully extend. SAX-7/L1CAM is a conserved neuron-glia adhesion molecule, GRDN-1 is a conserved cytoskeletal adaptor, and MAGI-1 is a conserved scaffolding protein. Each of these proteins is associated with AJs in epithelia; glial-specific depletion of the core AJ protein cadherin (HMR-1) also causes the same defects, leading to the idea that AJs mediate dendrite-glia attachments. The Aims of this study are to (Aim 1) determine the role of AJs in dendrite-glia interaction using localization and cell-specific depletion experiments; (Aim 2) define the molecular roles of SAX- 7, GRDN-1, and MAGI-1 using in vivo rescue and in vitro binding assays; and (Aim 3) identify additional players in this novel junction using genetic screens, focusing initially on a MAP kinase and a formin-related protein as new players. The longer-term goal is to study these proteins in a mouse glia model, thus translating genetic discoveries from C. elegans to mammalian brain.

抽象的 神经元与神经胶质之间的细胞间相互作用会影响多种神经疾病， 从自闭症和精神分裂症到肌萎缩性侧面硬化症（ALS）和阿尔茨海默氏病， 以及对中风和脑外伤的反应。一些最重要的 相互作用发生在突触中，其中附有接收信息的树突状刺 到星形胶质细胞神经胶质。组装这些细胞附着的分子机制保留 由于与哺乳动物大脑的复杂性相关的挑战，难以捉摸。 这项研究的目的是使用树突的创新模型克服这些挑战。 果岭梭菌中的胶质相互作用。如下所述，中心假设是树突状 - 绿色 触点是由上皮粘附连接（AJ）的蛋白质介导的。因此，这个 研究在于两个领域的交集：将AJ的知识从上皮生物学应用于A 长期存在的神经胶质生物学问题，相反，利用神经胶质生物学的多样性 研究如何在上皮外的细胞环境中部署AJ蛋白。 在初步数据中，创新方法可以分析一类新的Dendrite-Glia 接触。两个神经元，urx和袋子，将树突延伸到鼻子，在鼻子上紧密包裹 单个定义的神经胶质细胞，侧向ILSO神经胶质。遗传筛查确定了因子（SAX-7，GRDN- 1，magi-1）在胚胎伸长期间用神经胶质作用将这些树突锚定在鼻子上。 当这些因素被破坏时，开发树突从鼻子脱离而无法完全 延长。 SAX-7/L1CAM是一种保守的神经元-GLIA粘附分子，GRDN-1是保守的 细胞骨架适配器和MAGI-1是一种保守的脚手架蛋白。这些蛋白质中的每一个都是 与上皮的AJ相关；核AJ蛋白钙粘蛋白（HMR-1）的神经胶质特异性耗竭 还会导致相同的缺陷，从而导致AJS介导树突状固定的想法。 这项研究的目的是（AIM 1）使用AJ在使用Dendrite-Glia相互作用中的作用 定位和细胞特异性耗竭实验； （AIM 2）定义萨克斯 7，GRDN-1和MAGI-1使用体内救援和体外结合测定； （目标3）确定 这个小说中的其他玩家使用遗传屏幕，最初集中在地图激酶上 以及作为新玩家的formin相关蛋白质。长期目标是研究这些蛋白质 小鼠神经胶质模型，从而将遗传发现从秀丽隐杆线虫转化为哺乳动物大脑。