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

基本信息

批准号：
10221016
负责人：
Jessica E Treisman
金额：
$ 25.43万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221016
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 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

项目摘要

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.

概括细胞之间的粘附对于上皮组织和神经的发展很重要在两种情况下，都发现电路和越来越多的粘附分子起作用。为了例如，辅助（SDK）是免疫球蛋白家族成员，可介导特定之间的粘附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粘附连接（TAJS）的组装，在三个上皮细胞的点控制张力满足，除了在视觉运动检测电路中的功能外。该提议将调查 SDK本地化和功能在上下文中的机制，并探索可能的连接他们。第一个目的将调查SDK将其定位到TAJS的定位是否由其拟合度驱动三维结构及其几何形状。 SDK已显示出募集多鸡油和独木舟，将肌动蛋白丝的末端固定在泰姬陵上。但是，SDK也可以与波调节性相互作用复杂，促进肌动蛋白分支。这种相互作用是SDK对SDK的影响的假设将测试连接延长，而多chaetoid和独木舟促进结的缩短。酵母两个杂交屏幕将用于识别SDK募集到TAJS的其他因素。第二个 AIM将检查视觉系统中SDK的突触定位。扩展显微镜将用于确定SDK是否定位于TM9和T5神经元之间突触的特定子区域，和/或到T5树突上的特定位置。对SDK定位结构改变的影响 T5中的蛋白质和张力将进行测试。最后，SDK的上皮相互作用伙伴的可能性同样将研究突触时的共定位和功能。该探索性建议将提供深入了解新发现的Tajs的组装和功能，并可能揭示一个平行的结构突触。确定上皮和突触连接的共同特征将有助于我们了解影响或两种组织类型的发育障碍。