The Draper signaling pathway in Drosophila glial immune functions

神经胶质细胞是神经系统中的主要免疫细胞类型。对神经感染或创伤的反应 它们变得“反应性”，在基因表达和形态上经历刻板印象的变化。然而， 神经损伤或死亡的神经胶质反应的分子细节还知之甚少。 我们研究果蝇的胶质免疫功能，因为它有明确的胶质亚型，类似于 哺乳动物的神经胶质细胞，它可以进行遗传分析。这项建议的重点是果蝇神经胶质细胞的作用 以及新发现的死亡神经元胶质细胞吞噬中的Drpr受体，以及神经胶质细胞对神经元的反应 中枢神经系统损伤。DRPR编码一种吞噬受体，对于神经胶质细胞身体的移除是必不可少的； 在轴突被包裹后，drpr受体在神经胶质细胞中也被转录上调。 断绝关系。我们将采用分子遗传学的方法来了解DRPR如何在神经胶质反应中发挥作用 神经损伤、损伤轴突的胶质细胞吞噬以及神经元-神经胶质细胞相互作用的其他机制 神经创伤。我们的具体目标是： 1)描述胚胎中枢神经系统中的Draper功能：我们将定义Drpr和特定Drpr的角色 果蝇胚胎中枢神经系统细胞身体清除和神经胶质形态发生中的受体亚型。 2)定义神经损伤的神经胶质反应以及Draper在移除受损轴突中的作用：我们将定义 神经胶质细胞在神经损伤时的形态和分子变化，并决定了 损伤轴突摘除对drpr和神经胶质细胞的要求。 3)明确Wlds蛋白的细胞和分子作用：Weller变性缓慢(Wlds)蛋白 通过未知的机制保护受损的轴突免受退化。我们发现Wlds也可以 切断果蝇轴突的退化。我们将探索Wlds对果蝇的保护作用 轴突，以及Wlds表达对神经损伤的神经胶质反应的影响。 在果蝇和小鼠中，神经损伤后神经元-神经胶质细胞通讯的机制很可能是保守的， 由于果蝇的胶质细胞也变得活跃，Wlds可以保护果蝇被切断的轴突。刻画 中枢神经系统损伤后调节神经元和神经胶质功能的基因对于识别新的 治疗中枢神经系统损伤和神经系统疾病的途径。

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.