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.

总结 细胞间的粘附对于上皮组织和神经细胞的发育都是重要的。 电路和越来越多的粘附分子已经被发现在这两种情况下发挥作用。为 例如，Sidekicks（Sdks）是免疫球蛋白家族成员，其介导特异性抗体之间的粘附。 脊椎动物视网膜中的突触伴侣。果蝇Sdk最近被证明是一个枢纽， 三细胞粘附连接（tAJs）的组装，其控制三个上皮细胞 满足，除了它的功能在视觉运动检测电路。该提案将调查 机制的Sdk本地化和功能，在这两种情况下，并探讨可能的联系， 他们第一个目标是研究Sdk到tAJs的本地化是否是由其 三维结构及其几何形状。SDK已被证明可以招募多毛类和独木舟， 它将肌动蛋白丝的末端锚在tAJs上。然而，Sdk也可以与WAVE监管机制相互作用。 复合物，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。酵母 双杂交筛选将用于鉴定由Sdk募集至tAJs的其他因子。第二 目的是研究Sdk在视觉系统中的突触定位。扩增显微镜将用于 确定Sdk是否定位于Tm 9和T5神经元之间的突触的特定子区域， 和/或T5树突上的特定位置。结构改变对Sdk定位的影响 将测试T5中的蛋白质和张力。最后，上皮细胞与Sdk相互作用的可能性 还将研究其在突触处的共定位和功能。这一探索性建议将提供 深入了解新发现的tAJs的组装和功能，并可能揭示一种平行结构， 突触识别上皮和突触连接的共同特征将有助于我们 了解影响一种或两种组织类型的发育障碍。