Glial cell behavior in the developing visual system

描述（由申请人提供）：尽管与脑癌和神经系统修复具有巨大的临床相关性，但神经胶质细胞的发育和功能在脊椎动物和无脊椎动物神经生物学中受到的关注相对较少。在发育过程中，神经胶质细胞的正确定位是至关重要的建立在中枢神经系统的胚胎和视觉系统的果蝇，提出了重要的问题，有关的机制，控制增殖和迁移的神经胶质细胞的到来之前，不断增长的轴突和有关的线索，他们提出控制轴突的生长和寻路。一般来说，我们对体内控制胶质细胞迁移的信号和机制知之甚少，虽然在果蝇胚胎中发现了重要的胶质细胞来源的引导信号及其受体，但它们似乎都没有在视觉系统中发挥重要作用。我们研究了视网膜下神经胶质细胞的发育，这些神经胶质细胞随着光感受器的逐步分化而增殖并迁移到发育中的果蝇眼盘中，并研究了不同信号通路在控制神经胶质细胞行为中的作用。我们发现EGFr对视网膜下胶质细胞迁移具有非常显著的同种型特异性作用，而这种作用不是由经典的Ras-Raf-MAPK途径介导的。拟议的研究旨在开发改进的遗传和活体成像技术，用于研究增殖迁移细胞群，使用它们来阐明体内胶质细胞迁移的机制，并通过识别相关配体和效应物来剖析EGFr亚型在控制胶质细胞行为的不同方面中的作用;最后一个目标是使用分层反向遗传方法，使用FACS分选、基因芯片分析和RNA干扰，寻找参与控制神经胶质行为和神经胶质-神经元相互作用的其它RTK和其它受体。因此，拟议研究的目的是进一步开发和研究遗传系统中神经胶质细胞行为的急需模型，为神经胶质细胞中EGFr功能的新方面提供材料见解，并将分析扩展到EGFr的非经典途径以及其他RTK和受体，其最终目标是为人类恶性和再生情况的治疗干预提供新的靶点。

DESCRIPTION (provided by applicant): Despite enormous clinical relevance for brain cancer and nervous system repair, the development and function of glial cells has received relatively little attention in vertebrate and invertebrate neurobiology. During development, the correct positioning of glia is crucial for the establishment of neural connectivity in the CNS of the embryo and the visual system of Drosophila, raising important questions regarding the mechanisms controlling the proliferation and migration of glia prior to the arrival of growing axons and regarding the cues presented by them to control axonal growth and pathfinding. Generally, little is known about the signals and mechanisms that control glial migration in vivo, and while important glia-derived guidance cues and their receptors have been identified in the Drosophila embryo, none of them appear to play a major role in the visual system. We have investigated the development of the subretinal glia, which proliferate and migrate into the developing Drosophila eye disc concomitant with the progressive differentiation of photoreceptors, and examined the role of different signaling pathways in controlling glial cell behavior. We found that the EGFr has a very pronounced, isoform-specific effect on subretinal glial migration that is not mediated by the canonical Ras-Raf-MAPK pathway. The proposed research aims to develop improved genetic and live imaging techniques for studying proliferative migrating cell populations, to use them to illuminate the mechanisms of glial migration in vivo, and to dissect the role of the EGFr isoforms in controlling different aspects of glial behavior by identifying the relevant ligands and effectors; a final aim is to search for additional RTKs and other receptors involved in controling glial behavior and glia-neuron interactions, using a layered reverse genetic approach that employs FACS sorting, GeneChip analysis and RNA interference. The objective of the proposed study is thus to further develop and investigate a much needed model for glial cell behavior in a genetic system, to provide material insights into novel aspects of EGFr function in the glia, and to expand the analysis towards non-canonical pathways of the EGFr and to other RTKs and receptors, with the ultimate goal of providing new targets for therapeutic interference in both malignant and regenerative situations in humans.