Interactive processes in photoreceptor axon targeting

光感受器轴突靶向中的交互过程

• 批准号: 9796954
• 负责人: Jessica E Treisman
• 金额: $ 42.38万
• 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/9796954
• 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.

神经回路的开发需要神经元过程才能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会导致 可再现的分层组织简化了连接问题。例如，在果蝇中 视觉系统紫外线敏感R7光感受器轴突始终连接到其突触后DM8 髓质的M6层中的合作伙伴。先前的研究已经确定了R7所需的因素的正常因素 投影模式，但对环境中的细胞和分子提示知之甚少 认识。该建议的目的是通过识别形状的神经元和信号来缩小这一差距 延髓的环境和引导R7通过它。第一个目的是基于发现 仅当R7中还需要在R7中丢失和发现的Cub-LDL蛋白（面包）也需要 环境。确定在不同神经元中改变面包水平的后果将 区分两个假设：R7和DM8中的面包的匹配水平促进突触 它们之间的形成，或R7与其他表达面包的神经元竞争以访问其目标 层。其他实验将调查面包是否介导同粒细胞或异质粘附或 贩运其他分子到突触。第二个目的将检查如何在 切向投射神经元有助于分离髓质层。提出的实验 将确定Plexa是否充当自主引导切向神经元的受体，然后 向其他过程提供指导信息，或者作为一种本身是通过向内生长所认可的配体 髓质神经元和/或R7的过程。第三个目标将利用最近的转录组分析 确定富含DM8的细胞表面或分泌分子是必要的 用R7促进突触形成。最有趣的候选人将被选中以进一步分析 它的作用机理。这项研究中定义的细胞和分子相互作用可能揭示 适用于更复杂的神经回路的原则，并提供有关 自闭症和癫痫等神经发育障碍中缺陷的性质。