The Draper signaling pathway in Drosophila glial immune functions

描述（由申请人提供）：胶质细胞是神经系统中的主要免疫细胞类型。在响应神经感染或创伤，他们成为“反应”，经历刻板的基因表达和形态的变化。然而，神经胶质细胞对神经损伤或死亡的反应的分子细节知之甚少。我们在果蝇中研究神经胶质的免疫功能，因为它具有类似于哺乳动物神经胶质的明确定义的神经胶质亚型，并且适合于遗传分析。本研究的重点是果蝇胶质细胞和新发现的Drpr受体在胶质细胞吞噬死亡神经元中的作用，以及胶质细胞对中枢神经系统神经损伤的反应。Drpr编码神经元细胞尸体的胶质细胞去除所必需的吞噬受体; Drpr受体也在它们包裹的轴突被切断后在胶质细胞中有效地转录上调。我们将采取分子遗传学方法来了解Drpr如何在神经损伤的神经胶质反应中发挥作用，损伤轴突的神经胶质吞噬，以及神经创伤后神经元-神经胶质相互作用的其他机制。我们的具体目标是：1）表征德雷珀在胚胎中枢神经系统中的功能：我们将确定Drpr和特定Drpr受体亚型在果蝇胚胎中枢神经系统中细胞尸体去除和神经胶质形态发生中的作用。2)定义神经胶质细胞对神经损伤的反应和德雷珀在去除损伤轴突中的作用：我们将定义神经胶质细胞对神经损伤的反应所表现出的形态学和分子变化，并确定Drpr和神经胶质细胞在去除损伤轴突中的要求。3)定义Wlds蛋白的细胞和分子作用：Wallerian变性缓慢（Wlds）蛋白通过未知机制保护受损轴突免于变性。我们发现Wlds还可以使切断的果蝇轴突免于退化。我们将探讨Wlds介导的果蝇轴突保护，以及Wlds表达对神经损伤的神经胶质反应的影响。神经损伤后神经元-胶质细胞通讯的机制可能在果蝇和小鼠中很好地保存，因为果蝇胶质细胞也变得反应性，并且Wlds可以保护果蝇中切断的轴突。表征调节神经元和神经胶质功能的基因对CNS创伤的响应对于确定治疗CNS损伤和神经系统疾病的新途径是至关重要的。

DESCRIPTION (provided by applicant): Glia are the primary immune cell type in the nervous system. In response to neural infection or trauma they becoming "reactive", undergoing stereotypical changes in gene expression and morphology. However, the molecular details of glial responses to neural injury or death are poorly understood. We study glial immune functions in Drosophila because it has well-defined glial subtypes that resemble mammalian glia, and it is amenable to genetic analysis. This proposal focuses on the role of Drosophila glia and the newly-identified Drpr receptor in glial engulfment of dead neurons, and glial responses to neural injury in the CNS. Drpr encodes an engulfment receptor essential for glial removal of neuronal cell corpses; the Drpr receptor is also potently transcriptionally upregulated in glia after the axons they ensheath are severed. We will take a molecular genetic approach to understand how Drpr functions in glial responses to neural injury, glial engulfment of injured axons, and additional mechanisms of neuron-glia interactions after neural trauma. Our specific aims are: 1) Characterize Draper functions in the embryonic CNS: We will define the role for Drpr and specific Drpr receptor isoforms in cell corpse removal and glial morphogenesis in the Drosophila embryonic CNS. 2) Define glial responses to neural injury and roles for Draper in removing injured axons: We will define morphological and molecular changes exhibited by glia in response to neural injury, and determine the requirements for Drpr and glia in the removal of injured axons. 3) Define the cellular and molecular action of Wlds protein: The Wallerian degeneration slow (Wlds) protein protects injured axons from degeneration by unknown mechanisms. We found that Wlds can also spare severed Drosophila axons from degeneration. We will explore Wlds-mediated protection of Drosophila axons, and the consequences of Wlds expression on glial responses to neural injury. Mechanisms of neuron-glia communication after neural injury are likely well-conserved in flies and mice, since Drosophila glia also become reactive and Wlds can protect severed axons in flies. Characterizing genes that regulate neuronal and glial function in response to CNS trauma is essential to identify new avenues for the treatment of CNS injury and neurological disease.