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.

摘要 神经元和胶质细胞之间的细胞间相互作用影响着各种神经疾病， 从自闭症和精神分裂症到肌萎缩侧索硬化症(ALS)和阿尔茨海默病， 以及对中风和创伤性脑损伤的反应。一些最重要的 相互作用发生在突触上，接收信息的树突连接在那里 到星形细胞胶质细胞。组装这些细胞间连接的分子机制仍然存在 这是难以捉摸的，因为与哺乳动物大脑的复杂性有关的挑战。 这项研究的目标是使用一种创新的树枝晶模型来克服这些挑战- 线虫中神经胶质细胞的相互作用。如下所述，中心假说是树突-胶质细胞 接触是由上皮细胞中的黏附连接(AJs)蛋白介导的。因此，这一点 这项研究位于两个领域的交叉点：将上皮生物学中的AJ知识应用于 胶质生物学中长期存在的问题，反过来，利用神经胶质生物学的多样性来 研究AJ蛋白如何部署在上皮细胞外的细胞环境中。 在初步数据中，创新的方法使得能够分析一类新的树突-胶质细胞 联系。URX和BAG两个神经元将树突延伸到鼻子，在那里它们紧密地包裹在一起 单个明确的神经胶质细胞，外侧白质胶质细胞。基因筛查确定的因子(SAX-7、GRDN- 1，MAGI-1)，在胚胎伸长过程中，它作用于胶质细胞，将这些树突固定在鼻子上。 当这些因素被破坏时，发育中的树突从鼻子上分离，不能完全 延伸。SAX-7/L1CAM是一种保守的神经元-胶质细胞黏附分子，GRDN-1是一种保守的 MAGI-1是一种保守的支架蛋白。这些蛋白质中的每一个都是 与上皮AJs相关；核心AJ蛋白钙粘蛋白(HMR-1)的胶质特异性缺失 也会导致同样的缺陷，导致认为AJs介导了树突-神经胶质细胞的附着。 本研究的目的是(目标1)确定AJs在树突-神经胶质细胞相互作用中的作用 定位和细胞特异性耗竭实验；(目标2)确定SAX-2的分子作用 7、GRDN-1和MAGI-1，采用体内挽救和体外结合试验；和(目标3)鉴定 在这个新的连接中的其他参与者使用遗传屏幕，最初专注于MAP激酶 和一种与福尔明相关的蛋白质作为新的参与者。更长期的目标是研究这些蛋白质 一种小鼠神经胶质模型，从而将线虫的基因发现转化为哺乳动物的大脑。