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

• 批准号: 9360542
• 负责人: Jessica P Douthit
• 金额: $ 3.48万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/9360542
• 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; Immune response; Intelligence; Length; Ligands; Light; Low Density Lipoprotein Receptor; Mediating; Modeling; Mosaicism; Mutation; Nervous system structure; Neurodevelopmental Disorder; Neurons; Neurophysiology - biologic function; Neuropilins; Organism; Pattern; Phenotype; Photoreceptors; Presynaptic Terminals; Process; Proteins; RNA Interference; 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; immunoregulation; insight; knock-down; nervous system development; neural circuit; novel; null mutation; overexpression; plexin; premature; receptor; retinotopic; tumor progression; visual map; visual processing

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 复杂神经回路的形成必须在发育过程中得到精确控制， 神经系统轴突通过检测长距离和短距离信号来定位目标 由环境中的细胞呈现，可以作为引诱剂或排斥剂。轴突缺陷 引导和瞄准可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残疾。果蝇的视觉系统 是研究轴突导向和神经回路基本机制的极好模型系统 阵R7和R8光感受器的末端负责色觉的不同方面， 被分隔成延髓的不同目标层，延髓是大脑中视觉处理的中心区域。 个脑袋光感受器也必须以视网膜定位方式投射，以保持对视网膜的精确表示。 大脑中的视野。在筛选控制颜色感光轴突的分子时， 使用RNAi靶向敲低大脑中的丛蛋白A（plexA）， 过早地终止于延髓的R8靶层，并且不能扩展它们的轴突末端。一 由编码外显子中的Minos元件插入引起的plexA（plexAMb 09499）中的蛋白质无效突变， 对R7轴突也有同样的影响。神经元需要plexA，但光感受器不需要，R7才能到达 正确的目标层。PlexA蛋白在靠近这一靶层的地方表达，表明它可能起作用， 作为R7轴突的吸引信号，与其在排斥L3板层神经元轴突中的已知作用相反 从这一层。将使用镶嵌分析来确认这是PlexA作用的位点。 光感受器中PlexA或缺乏胞质结构域的截短形式的过表达导致 神经纤维束过度收缩和轴突提前终止这种错误表达表型将是 用于表征PlexA作用的机制，并检验PlexA作为 光感受器的吸引或粘附信号。已知的PlexA的受体和配体，脑信号蛋白- 1a，对于R7光感受器的正常靶向是不需要的。我们将调查PlexA是否 与未表征的CUB结构域蛋白CG 6024相互作用;敲低CG 6024， 使用RNAi的光受体也破坏R7靶向。PlexA的同源物已经在 组织的脊椎动物视网膜，和丛蛋白家族成员也参与调节， 免疫反应，心脏和血管形成，甚至癌症的进展。初步结果 这表明PlexA通过一种新的信号传导机制控制R7靶向， 前所述因此，这项工作可能会提供新的见解控制机制， 高等生物的各种发育和疾病过程。