Interactive processes in photoreceptor axon targeting

神经回路的发育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。不同细胞类型的过程之间的动态相互作用通常会导致 可重复的分层组织简化了连接问题。例如，在果蝇中 视觉系统中，紫外线敏感的 R7 光感受器轴突始终连接到其突触后 Dm8 髓质 M6 层的伙伴。之前的研究已经确定了 R7 正常运行所需的因素 投影模式，但人们对它所在环境中的细胞和分子线索知之甚少。 认识。该提案的目标是通过识别神经元和信号来缩小这一差距 髓质的环境并引导 R7 通过它。第一个目标是基于以下发现： 仅当 CUB-LDL 蛋白 Lost and Find (Loaf) 也存在于 R7 中的其他细胞中时，它才是 R7 中所需要的。 环境。确定不同神经元组中 Loaf 水平变化的后果将 区分两个假设：R7 和 Dm8 中 Loaf 的匹配水平促进突触 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 层。其他实验将研究 Loaf 是否介导同性或异性粘附或 将其他分子运输到突触。第二个目标将检查 Plexin A (PlexA) 如何在 切向突出的神经元有助于髓质层的分离。拟议的实验 将确定 PlexA 是否充当自主引导切向神经元的受体，然后 为其他过程提供指导信息，或作为本身被向内生长识别的配体 髓质神经元和/或 R7 的突起。第三个目标将利用最近的转录组分析 确定哪些富含 Dm8 的细胞表面或分泌分子对于 促进 R7 突触形成。将选择最有趣的候选人进行进一步分析 其作用机制。这项研究中定义的细胞和分子相互作用可能揭示 这些原理将适用于更复杂的神经回路的组装，并提供深入了解 自闭症和癫痫等神经发育障碍的缺陷的本质。

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.