Specialized junctions in the development of epithelia and neural circuits

上皮细胞和神经回路发育中的特殊连接

• 批准号: 10040885
• 负责人: Jessica E Treisman
• 金额: $ 21.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040885
• 关键词: Abnormal Cell; Actins; Adherens Junction; Adhesions; Affect; Binding; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cells; Chickens; Complex; Dendrites; Detection; Development; Diffusion; Disease; Drosophila genus; Epithelial; Epithelial Cells; Epithelium; Family member; Gastrointestinal tract structure; Genetic Diseases; Geometry; Goals; Homologous Gene; Immunoglobulins; Inflammatory Bowel Diseases; Intercellular Junctions; Interneurons; Invertebrates; Investigation; Kidney; Knowledge; Learning; Link; Location; Maintenance; Mechanics; Mediating; Microfilaments; Microscopy; Nature; Neoplasm Metastasis; Nervous system structure; Neurons; Organ; PDZ protein; Phase; Population; Proteins; Research; Retina; Role; Septate; Skin; Structure; Synapses; System; Testing; Tight Junctions; Time; Tissues; Visual Motion; Visual system structure; Yeasts; afadin; autism spectrum disorder; developmental disease; improved; insight; neural circuit; presynaptic; recruit; screening; seal; solute; synaptogenesis; three dimensional structure; tumor; yeast two hybrid system

Summary Adhesion between cells is important for the development of both epithelial tissues and neural circuits, and a growing number of adhesion molecules have been found to act in both contexts. For example, Sidekicks (Sdks) are immunoglobulin family members that mediate adhesion between specific synaptic partners in the vertebrate retina. Drosophila Sdk was recently shown to act as a hub for the assembly of tricellular adherens junctions (tAJs), which control tension at points where three epithelial cells meet, in addition to its function in the visual motion detection circuit. This proposal will investigate the mechanisms of Sdk localization and function in both contexts and explore possible connections between them. The first aim will investigate whether the localization of Sdk to tAJs is driven by the fit between its three-dimensional structure and their geometry. Sdk has been shown to recruit Polychaetoid and Canoe, which anchor the ends of actin filaments, to tAJs. However, Sdk can also interact with the WAVE regulatory complex, which promotes actin branching. The hypothesis that this interaction underlies the effect of Sdk on junction lengthening, while Polychaetoid and Canoe promote junction shortening, will be tested. A yeast two-hybrid screen will be used to identify additional factors that are recruited to tAJs by Sdk. The second aim will examine the synaptic localization of Sdk in the visual system. Expansion microscopy will be used to determine whether Sdk localizes to specific subregions of synapses between the Tm9 and T5 neurons, and/or to a specific location on T5 dendrites. The effect on Sdk localization of structural alterations in the protein and of tension in T5 will be tested. Finally, the possibility that epithelial interaction partners of Sdk also colocalize and function with it at synapses will be investigated. This exploratory proposal will provide insight into the assembly and function of the newly discovered tAJs, and may reveal a parallel structure at synapses. Identifying the common features of epithelial and synaptic junctions will contribute to our understanding of developmental disorders that affect either or both tissue types.

摘要 细胞间的黏附对上皮组织和神经的发育都很重要 越来越多的黏附分子被发现在这两种情况下都起作用。为 例如，Sidekicks(SDK)是免疫球蛋白家族成员，在特定的 脊椎动物视网膜中的突触伙伴。果蝇SDK最近被证明是 三细胞黏附连接(TAJ)的组装，它控制三个上皮细胞之间的张力 Meet，除了其在视觉运动检测电路中的功能外。这项提案将调查 SDK在两种环境中的本地化和功能机制，并探索两者之间可能的联系 他们。第一个目标将调查SDK到tAJ的本地化是否是由其 三维结构及其几何形状。SDK已经被证明可以招募多毛类和独木舟， 它将肌动蛋白细丝的末端固定在tAJ上。不过，SDK也可以与浪潮进行互动监管 复合体，促进肌动蛋白分支。假设这种相互作用是SDK对 连接延长，而多毛类和独木舟促进连接缩短，将进行测试。一种酵母 将使用双混合筛选来识别SDK招募到tAJ的额外因素。第二 AIM将检查SDK在视觉系统中的突触定位。膨胀显微镜将被用来 确定SDK是否定位于Tm9和T5神经元之间突触的特定亚区， 和/或T5树突上的特定位置。的结构变化对SDK本地化的影响 将测试T5中的蛋白质和张力。最后，SDK上皮交互伙伴的可能性 此外，还将研究它在突触中的共定位和功能。这项探索性的建议将提供 深入了解新发现的tAJ的组装和功能，并可能在 突触。识别上皮和突触连接的共同特征将有助于我们的 了解影响其中一种或两种组织类型的发育障碍。