Defining Glial Programs that Support Adult Photoreceptor Form and Function

描述（由申请人提供）：尽管神经胶质细胞在神经发育和功能中起着重要作用，但我们对神经胶质细胞功能的遗传和分子途径的理解仍然非常有限。大多数胶质细胞亚型有助于神经元存活，并且胶质细胞功能障碍与大多数神经退行性疾病相关。在脊椎动物视网膜中，放射状M？ller胶质细胞作为成体神经干细胞的来源，控制组织稳态、神经保护甚至再生，但它们对光损伤的反应性胶质反应导致视网膜变性。因此，阐明在视觉系统老化和疾病期间介导胶质细胞-神经元相互作用、神经元保护和支持的分子途径和机制是指导临床研究的基础。对果蝇神经系统中胶质细胞谱系的详细分析揭示了与许多脊椎动物胶质细胞亚型相似的细胞。然而，令人惊讶的是，在果蝇复眼中还没有确定内在的神经胶质细胞群，果蝇复眼是一个深入研究的视觉系统，其中发现了无数保守的生物学途径。在这里，结合细胞特异性基因敲除，转录组学和电生理学方法，我们提供的证据表明，锥细胞（CC），一个子集的细胞在蝇眼分泌角膜透镜，也提供了至关重要的稳态支持功能，确保和维持适当的感光功能。此外，我们表明，这种胶质相关的支持需要进化保守的神经干细胞和胶质细胞生成因子，Prospero（优点，脊椎动物Prox 1）。在目的1中，我们提出了测试的假设，CC服务胶质支持细胞的功能，分析在何种程度上CC介导的保护功能特性的M？ller胶质细胞在脊椎动物视网膜。在目标2中，为了确定参与神经保护的基因，我们将定义CC中的Pros-regulated networks，这些网络对于防止成年人眼中光诱导的感光细胞变性至关重要。 结合起来，这些研究的完成将建立一个新的实验范式，并开发必要的分子，遗传，形态学和生理学工具，以快速解剖基因调控网络与果蝇遗传学的精确度神经胶质细胞依赖性神经保护。

DESCRIPTION (provided by applicant): Despite the essential roles of glia in neural development and function, our understanding of the genetic and molecular pathways underlying glial functions is still very limited. Most glial subtypes contribute to neuronal survival, and glil dysfunction is associated with most neurodegenerative conditions. In the vertebrate retina, the radial M¿ller glia govern tissue homeostasis, neuroprotection and even regeneration, as the source of adult neural stem cells, but their reactive gliotic response to light damage leads to retinal degeneration. Therefore, elucidating the molecular pathways and mechanisms that mediate glia-neuron interactions, neuronal protection and support during visual system aging and disease is fundamental to guide clinical research. Detailed analysis of glial lineages in the Drosophila nervous system has revealed cells analogous to many vertebrate glial subtypes. Surprisingly, however, no intrinsic glial cell population has yet been defined in the Drosophila compound eye, a deeply studied visual system in which innumerable conserved biological pathways have been discovered. Here, combining cell-specific genetic knockdowns, transcriptomics and electrophysiological methods, we provide evidence that cone cells (CCs), a subset of cells in the fly eye known to secrete the corneal lens, also provide crucial homeostatic support functions that ensure and maintain proper photoreceptor function. Furthermore, we show that this glia-related support requires the evolutionarily conserved neural stem cell and gliogenic factor, Prospero (Pros, vertebrate Prox1). In Aim 1, we propose to test the hypothesis that CCs serve glial support cell functions, assaying the extent to which CCs mediate protective functions characteristic of M¿ller glia in the vertebrate retina. In Aim 2, to identify genes involed in neuroprotection, we will define Pros-regulated networks in CCs that are critical for preventing light-induced photoreceptor degeneration in the adult eye. Combined, the completion of these studies would establish a new experimental paradigm and develop the necessary molecular, genetic, morphological and physiological tools to rapidly dissect gene regulatory networks underlying glia-dependent neuroprotection with the precision of Drosophila genetics.