Functional analysis of the Drosophila axon guidance receptor Robo2

项目摘要/摘要 在神经系统发育和损伤后再生的过程中，神经通路形成 通过迁移细胞外线索引导的神经元轴突。尽管许多人 我们的理解是，已经确定了调节轴突引导的主要信号通路 个别基因影响特定轴突引导结果的机制 仍然是有限的。在具有复杂神经系统的动物中，如昆虫和哺乳动物， 来自保守信号通路的单个配体和受体可以促进不同的或 甚至在不同的神经元轴突群体中也会出现相反的结果。这项提议使用的是水果 以果蝇为模型来解决单个基因如何 指定不同的轴突引导结果。进化保守的环形交叉口(ROBO) 轴突引导受体家族控制多个不同的轴突引导结果 发育中的果蝇胚胎中枢神经系统。这项拟议的研究需要 果蝇可用的分子和遗传工具在剖析机制方面的优势 个体ROBO受体的不同轴突引导活动的基础。该项目将使用 结构/功能基因修饰方法来表征功能结构域 有助于单个ROBO受体的轴突引导活动，将研究 ROBO基因在特定神经元群体中的转录调控有助于特定的 轴突指导决定，并将测试可能解释 受体在不同轴突引导环境中的作用(S)。拟议的研究将提供洞察力 单个轴突引导基因如何指定不同的发育结果，识别 可能在进化上保守的机制，可能在其他动物身上运行，包括 在人类中，Robo受体家族的成员也是轴突引导的关键调节者， 并可能提出新的策略，以恢复适当的调节轴突指导在 神经系统损伤、修复和再生的背景。

Project Summary/Abstract During nervous system development and post-injury regeneration, nerve pathways are formed by migrating neuronal axons which are guided by extracellular cues. Although many of the major signaling pathways that regulate axon guidance have been identified, our understanding of the mechanisms by which individual genes influence specific axon guidance outcomes remains limited. In animals with complex nervous systems, such as insects and mammals, individual ligands and receptors from conserved signaling pathways can promote diverse or even opposing outcomes in different populations of neuronal axons. This proposal uses the fruit fly Drosophila melanogaster as a model to address the question of how individual genes can specify diverse axon guidance outcomes. The evolutionarily conserved Roundabout (Robo) family of axon guidance receptors control multiple distinct axon guidance outcomes in the developing Drosophila embryonic central nervous system (CNS). The proposed research takes advantage of the molecular and genetic tools available in Drosophila to dissect the mechanisms underlying the diverse axon guidance activities of individual Robo receptors. The project will use structure/function gene modification approaches to characterize the functional domains that contribute to the axon guidance activities of individual Robo receptors, will investigate how the transcriptional regulation of robo genes in specific neuronal populations contributes to specific axon guidance decisions, and will test candidate mechanisms that may account for the receptors’ role(s) in different axon guidance contexts. The proposed research will provide insight into how individual axon guidance genes can specify diverse developmental outcomes, identify potentially evolutionarily conserved mechanisms that may operate in other animals, including humans, where members of the Robo receptor family are also key regulators of axon guidance, and may suggest novel strategies for restoring proper regulation of axon guidance in the contexts of nervous system injury, repair, and regeneration.