Functional analysis of the Drosophila axon guidance receptor Robo2

项目总结/摘要 在神经系统发育和损伤后再生过程中， 通过细胞外信号引导神经元轴突迁移。尽管许多 调节轴突引导的主要信号通路已经被确定，我们的理解是， 单个基因影响特定轴突导向结果的机制 仍然有限。在具有复杂神经系统的动物中，如昆虫和哺乳动物， 来自保守信号传导途径的单个配体和受体可以促进多种或 甚至在不同的神经元轴突群体中产生相反的结果。这个建议用水果 以果蝇为模型来解决单个基因如何 指定不同轴突引导结果。进化保守的回旋处（Robo） 轴突导向受体家族控制多个不同的轴突导向结果， 发育中的果蝇胚胎中枢神经系统（CNS）。拟议的研究需要 利用果蝇中可用的分子和遗传工具来剖析 这是个体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， 有助于个体Robo受体的轴突指导活动，将研究如何 特定神经元群体中robo基因的转录调控有助于特定的神经元细胞的分化。 轴突指导决定，并将测试候选机制，可能占 受体在不同轴突引导环境中的作用。拟议的研究将提供洞察力 研究单个轴突指导基因如何指定不同的发育结果， 可能在其他动物中起作用的潜在进化保守机制，包括 人类，其中Robo受体家族的成员也是轴突引导的关键调节剂， 并可能提出新的策略，以恢复正常的调节轴突的指导， 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.