Interactive processes in photoreceptor axon targeting

光感受器轴突靶向中的交互过程

• 批准号: 10412062
• 负责人: Jessica E Treisman
• 金额: $ 42.83万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412062
• 关键词: Adhesions; Adhesives; Affect; Axon; Binding; Biological Models; Brain; Cell Adhesion Molecules; Cell surface; Cells; Collection; Color; Color Visions; Complex; Cues; Defect; Development; Drosophila genus; Ensure; Environment; Epilepsy; Event; Eye; Genes; Genetic Screening; Goals; Growth Cones; Human; Integral Membrane Protein; Interneurons; LAR tyrosine phosphatase receptor; Lead; Ligands; Light; Logic; Low-Density Lipoproteins; Mediating; Molecular; Mutation; Nature; Neurites; Neurodevelopmental Disorder; Neurons; Pattern; Photoreceptors; Process; Protein Tyrosine Phosphatase; Proteins; Reproducibility; Role; Semaphorins; Shapes; Signal Transduction; Structure; Synapses; System; Testing; Visual system structure; autism spectrum disorder; base; cell type; experimental study; insight; mutant; nervous system development; neural circuit; plexin; postsynaptic; receptor; synaptogenesis; tool; trafficking; transcriptomics; ultraviolet

Neural circuit development requires neuronal processes to find the correct synaptic partners within a complex environment. Dynamic interactions between processes from different cell types often result in a reproducible layered organization that simplifies this connectivity problem. For example, in the Drosophila visual system the ultraviolet-sensitive R7 photoreceptor axons always connect to their post-synaptic Dm8 partners in the M6 layer of the medulla. Previous studies have identified factors required in R7 for its normal projection pattern, yet little is known about the cellular and molecular cues in the environment that it recognizes. The goal of this proposal is to close this gap by identifying the neurons and signals that shape the environment of the medulla and guide R7 through it. The first aim is based on the discovery that the CUB-LDL protein Lost and found (Loaf) is required in R7 only when it is also present in other cells in the environment. Determining the consequences of varying the levels of Loaf in different sets of neurons will distinguish between two hypotheses: that matching levels of Loaf in R7 and Dm8 promote synapse formation between them, or that R7 competes with other Loaf-expressing neurons for access to its target layer. Other experiments will investigate whether Loaf mediates homophilic or heterophilic adhesion or traffics other molecules to the synapse. The second aim will examine how Plexin A (PlexA) expressed on tangentially projecting neurons contributes to the separation of medulla layers. The proposed experiments will determine whether PlexA acts as a receptor to autonomously guide tangential neurons, which then provide guidance information to other processes, or as a ligand that is itself recognized by the ingrowing processes of medulla neurons and/or R7. The third aim will make use of a recent transcriptomic analysis to determine which of the cell-surface or secreted molecules that are enriched in Dm8 are necessary to promote synapse formation with R7. The most interesting candidate will be selected for further analysis of its mechanism of action. The cellular and molecular interactions defined in this study are likely to reveal principles that will be applicable to the assembly of more complex neural circuits, and to provide insight into the nature of the defects in neurodevelopmental disorders such as autism and epilepsy.

神经回路的发展需要神经元过程在神经元内找到正确的突触伙伴。 复杂的环境来自不同细胞类型的过程之间的动态相互作用通常导致 可复制的分层组织，简化了这种连接问题。例如，在果蝇中， 在视觉系统中，对紫外线敏感的R7光感受器轴突总是连接到它们的突触后Dm 8 在髓质的M6层中的伴侣。以前的研究已经确定了R7正常生长所需的因素， 投射模式，但很少有人知道的细胞和分子线索的环境，它 承认。这项提案的目标是通过识别形成的神经元和信号来缩小这一差距 延髓的环境，并引导R7通过它。第一个目标是基于发现， CUB-LDL蛋白质Lost and found（Loaf）仅在R7中也存在于其他细胞中时才需要。 环境确定不同神经元中Loaf水平变化的后果将 区分两种假设：R7和Dm 8中Loaf的匹配水平促进突触 它们之间的形成，或者R7与其他Loaf表达神经元竞争进入其目标 层.其他实验将研究Loaf是否介导嗜同性或嗜异性粘附， 将其他分子运送到突触。第二个目标是研究丛蛋白A（PlexA）在细胞表面表达的情况。 切向投射的神经元有助于髓质层的分离。拟议的实验 将确定PlexA是否作为受体自主引导切向神经元，然后 为其他过程提供指导信息，或者作为自身被向内生长的细胞识别的配体， 延髓神经元和/或R7的突起。第三个目标将利用最近的转录组学分析， 确定哪些细胞表面或分泌的分子富集在Dm 8中是必需的， 促进与R7的突触形成。将选择最感兴趣的候选人进行进一步分析， 其作用机制。本研究中定义的细胞和分子相互作用可能揭示 这些原则将适用于更复杂的神经回路的组装，并提供对 自闭症和癫痫等神经发育障碍的缺陷性质。