Adherens junction proteins in neuron-glia interactions

摘要 神经元和神经胶质之间的细胞间相互作用影响多种神经系统疾病， 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，接受信息的树突棘附着在突触上。 到星形胶质细胞组装这些细胞-细胞附着的分子机制仍然存在 由于哺乳动物大脑的复杂性带来的挑战， 本研究的目标是利用一种创新的枝晶模型来克服这些挑战， 胶质细胞相互作用在C.优雅如下所述，中心假设是树突-胶质细胞 接触由来自上皮中粘附连接（AJs）的蛋白质介导。因此， 研究在于两个领域的交叉点：将上皮生物学的AJs知识应用于 这是神经胶质生物学中的一个长期存在的问题，相反，利用神经胶质生物学的多样性， 研究AJ蛋白如何在上皮细胞外的细胞环境中部署。 在初步的数据中，创新的方法使分析一类新的树突神经胶质细胞成为可能。 contact.两个神经元URX和BAG将树突延伸到鼻子，在那里它们紧密地包裹着 一个单独的胶质细胞，外侧IL 50胶质细胞。基因筛选确定的因素（SAX-7，GRDN-1， 1，MAGI-1），其在神经胶质中起作用以在胚胎伸长期间将这些树突锚在鼻处。 当这些因素被破坏时，发育中的树突从鼻子上脱离， 伸展。SAX-7/L1 CAM是一种保守的神经胶质细胞粘附分子，GRDN-1是一种保守的神经胶质细胞粘附分子。 MAGI-1是一种保守的支架蛋白。每一种蛋白质都是 与上皮中的AJs相关;核心AJ蛋白钙粘蛋白（HMR-1）的胶质细胞特异性耗竭 也会导致同样的缺陷，导致AJs介导树突-胶质细胞附着的想法。 本研究的目的是（目的1）确定AJs在树突-胶质细胞相互作用中的作用， 定位和细胞特异性耗竭实验;（目的2）定义SAX的分子作用- 7、GRDN-1和MAGI-1;以及（目的3）鉴定 在这个新的交界处使用遗传筛选，最初集中在MAP激酶， 和一种与formin相关的蛋白质作为新的参与者。长期目标是研究这些蛋白质， 小鼠神经胶质细胞模型，从而将C.哺乳动物的大脑。

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.