A Novel Role For Plexin A in Photoreceptor Axon Targeting

Plexin A 在光感受器轴突靶向中的新作用

基本信息

批准号：
9195310
负责人：
Jessica P Douthit
金额：
$ 3.43万
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：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9195310
关键词：
Adhesives Adult Alternative Splicing Axon Binding Biological Models Brain Cell Surface Proteins Cells Clone Cells Code Color Color Visions Complex Cytoplasmic Tail DNA Insertion Elements Data Defect Development Disease Drosophila genus Environment Epilepsy Exons Family member Genes Genetic Genetic Screening Heart Homologous Gene Immune response Intelligence Length Ligands Light Low Density Lipoprotein Receptor Maps Mediating Modeling Mutation Nervous system structure Neurodevelopmental Disorder Neurons Neuropilins Organism Pattern Phenotype Photoreceptors Presynaptic Terminals Process Proteins RNA Interference RNA Splicing Regulation Retina Role Schizophrenia Semaphorins Signal Transduction Site Synapses Tertiary Protein Structure Testing Transcript Visual Visual Fields Visual system structure Work angiogenesis autism spectrum disorder axon guidance disability fly genome editing insight knock-down nervous system development neural circuit novel null mutation overexpression plexin premature receptor retinotopic tumor progression visual process visual processing

项目摘要

Project Summary Formation of complex neural circuits must be precisely controlled during the development of the nervous system. Axons navigate to their targets by detecting both long-range and short-range signals presented by cells in the environment that can act as attractants or repellants. Defects in axon guidance and targeting can result in a number of neurodevelopmental disorders, such as epilepsy, schizophrenia, Autism Spectrum Disorders, and intelligence disabilities. The Drosophila visual system is an excellent model system for studying the basic mechanisms of axon guidance and neural circuit formation. The terminals of R7 and R8 photoreceptors, responsible for different aspects of color vision, are segregated into distinct target layers of the medulla, a central region of visual processing in the brain. Photoreceptors also must project in a retinotopic manner to maintain a precise representation of the visual field within the brain. In a screen for molecules that control color photoreceptor axon targeting, knocking down plexin A (plexA) in the brain using RNAi caused R7 photoreceptors to prematurely terminate in the R8 target layer of the medulla and fail to expand their axon terminals. A protein null mutation in plexA (plexAMb09499) caused by a Minos element insertion in a coding exon has the same effect on R7 axons. plexA is required in neurons, but not in photoreceptors, for R7 to reach the correct target layer. PlexA protein is expressed close to this target layer, suggesting that it may act as an attractive signal for R7 axons, in contrast to its known role in repelling L3 lamina neuron axons from this layer. Mosaic analysis will be used to confirm that this is the site of PlexA action. Overexpression of PlexA or a truncated form lacking the cytoplasmic domain in photoreceptors results in hyperfasciculation and premature termination of their axons. This misexpression phenotype will be used to characterize the mechanism of PlexA action and test the hypothesis that PlexA acts as an attractive or adhesive signal for photoreceptors. The known receptor and ligand for PlexA, Semaphorin- 1a, is not required for normal targeting of R7 photoreceptors. We will investigate whether PlexA instead interacts with an uncharacterized CUB domain protein, CG6024; knocking down CG6024 in photoreceptors using RNAi also disrupts R7 targeting. Homologs of PlexA have been studied in the organization of the vertebrate retina, and Plexin family members also participate in regulation of the immune response, heart and vessel formation, and even the progression of cancer. Preliminary results suggest that PlexA controls R7 targeting through a novel signaling mechanism, distinct from those previously described. Therefore, this work may provide new insight into the mechanisms that control a variety of developmental and disease processes in higher organisms.

项目摘要在开发过程中必须精确控制复杂的神经回路的形成神经系统。轴突通过检测远程和短距离信号来导航到目标由细胞在环境中呈现，可以充当吸引者或驱虫剂。轴突中的缺陷指导和靶向可能导致许多神经发育障碍，例如癫痫，精神分裂症，自闭症谱系障碍和智力障碍。果蝇视觉系统是研究轴突指导和神经回路的基本机制的出色模型系统形成。 R7和R8光感受器的终端，负责色觉的不同方面，被隔离为髓质的不同目标层，髓质是视觉处理的中心区域脑。感光体还必须以视网膜量进行投射，以保持大脑内的视野。在控制颜色光感受器轴突的分子的屏幕中靶向，使用RNAi在大脑中击倒plexin A（Plexa）导致R7感光体过早终止在髓质的R8目标层中，无法扩展其轴突终端。一个由Minos元素在编码外显子中插入的PLEXA中的蛋白质零突变（Plexamb09499）对R7轴突的影响相同。在神经元中，需要PlexA，而在感光器中不需要Plexa才能达到R7 正确的目标层。 Plexa蛋白靠近该目标层，表明它可能作用作为R7轴突的有吸引力的信号，与其在排斥L3层神经元轴突中的已知作用相反从这个层。马赛克分析将用于确认这是Plexa作用的位置。在光感受器中缺少细胞质结构域的PLEXA或截短形式的过表达结果在高血管和轴突的过早终止中。这种Misexpression表型将是用于表征Plexa作用机制并检验Plexa充当的假设感光体的吸引力或粘合信号。 Plexa，Semaphorin-的已知受体和配体 1A，不需要正常的R7光感受器靶向。我们将调查是否相反与未表征的Cub结构蛋白CG6024相互作用；击倒CG6024 使用RNAi感受器也破坏R7靶向。 Plexa的同源物已在脊椎动物视网膜的组织和plexin家族成员也参与监管免疫反应，心脏和血管形成，甚至是癌症的进展。初步结果建议PLEXA通过一种新型信号传导机制来控制R7的靶向，与之不同先前描述的。因此，这项工作可能会为控制A的机制提供新的见解较高生物体的多种发育和疾病过程。