Interactive processes in photoreceptor axon targeting

摘要 神经回路的发育需要神经元过程来寻找正确的突触伙伴 环境复杂。来自不同细胞类型的进程之间的动态交互通常会导致 可重复的分层组织，简化了这一连接问题。例如，在果蝇中 视觉系统对紫外线敏感的R7感光轴突总是连接到它们的突触后Dm8 在延髓的M6层中的伙伴。以前的研究已经确定了R7正常所需的因素 投射模式，但对它所处环境中的细胞和分子线索知之甚少 认出了。这项提议的目标是通过识别神经元和信号来缩小这种差距 延髓的环境，并引导R7穿过它。第一个目标是基于这样一个发现： 只有在R7中也存在于其他细胞中时，才需要CUB-LDL蛋白失而复得(Loaf) 环境。确定不同神经元中不同的Loaf水平的后果将 区分两个假设：R7和Dm8中匹配的Loaf水平促进突触 它们之间的形成，或者R7与其他表达Loaf的神经元竞争接近其目标 一层。其他实验将调查Loaf是否介导了同嗜性或异嗜性粘连或 将其他分子输送到突触。第二个目标将研究丛状蛋白A(PlexA)是如何在 切线投射神经元有助于延髓层的分离。拟议中的实验 将确定PlexA是否作为一种受体自主引导切向神经元，然后 为其他过程提供指导信息，或作为自身被嵌入识别的配体 延髓神经元和/或R7的突起。第三个目标将利用最近的转录分析来 确定富含Dm8的细胞表面或分泌分子中的哪一种是必需的 促进R7的突触形成。最感兴趣的候选人将被选中进行进一步的分析 它的作用机制。这项研究中定义的细胞和分子相互作用很可能揭示 将适用于组装更复杂的神经电路的原则，并提供对 自闭症和癫痫等神经发育障碍的缺陷的性质。

Summary 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.