The Draper signaling pathway in Drosophila glial immune functions

描述(申请人提供)：神经胶质细胞是神经系统中的主要免疫细胞类型。作为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，神经损伤或死亡引起的神经胶质反应的分子细节却知之甚少。我们研究果蝇的胶质免疫功能是因为它有明确的胶质亚型，类似于哺乳动物的胶质细胞，而且它服从遗传分析。本研究的重点在于果蝇神经胶质细胞和新近发现的DRPR受体在胶质细胞吞噬死亡神经元中的作用，以及中枢神经系统对神经损伤的神经反应。Drpr编码一种吞噬受体，对神经胶质细胞身体的移除是必不可少的；drpr受体在轴突被鞘切断后，也在胶质细胞中转录上调。我们将采用分子遗传学的方法来了解DRPR如何在神经损伤后的神经胶质反应中发挥作用，胶质细胞吞噬受损的轴突，以及神经创伤后神经元-胶质细胞相互作用的其他机制。我们的具体目标是：1)研究Draper在胚胎CNS中的功能：我们将确定Drpr和特定的Drpr受体亚型在果蝇胚胎CNS中的细胞身体清除和神经胶质形态发生中的作用。2)明确神经损伤对胶质细胞的反应以及Draper在去除受损轴突中的作用：我们将定义神经损伤后胶质细胞表现出的形态和分子变化，并确定在去除受损轴突时对Drpr和胶质细胞的要求。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损伤轴突免受变性。我们发现Wlds还可以使果蝇切断的轴突免于退化。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。在果蝇和小鼠中，神经损伤后神经元-神经胶质细胞的通讯机制很可能是保守的，因为果蝇的神经胶质细胞也变得活跃，而Wlds可以保护果蝇中被切断的轴突。确定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确定治疗中枢神经系统损伤和神经系统疾病的新途径至关重要。

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.