Regulation of Glial Cell Size

 描述(申请人提供)：组织层的大小在器官发育过程中进行缩放。在神经系统中，神经元和胶质细胞的大小必须是协调的，特别是对于神经胶质细胞，如雪旺细胞和卫星细胞，它们与轴突或神经元胞体密切相关。雪旺细胞和卫星神经胶质细胞对神经损伤的不适当生长与慢性疼痛有关。尽管它很重要， 关于神经元和神经胶质细胞的生长是如何协调的，人们知之甚少。在果蝇中，至少有两种类型的胶质细胞通过增加DNA含量(倍体)来增加细胞大小，这是在动植物王国中产生大细胞的普遍策略。通过测量倍性来监测胶质细胞大小，通过改变倍性来改变胶质细胞生长的能力，为果蝇这个用于分析神经系统发育的强大工具包提供了额外的实验优势。我们建议利用果蝇神经系统中的倍性神经胶质生长来确定在发育过程中神经胶质细胞和神经元之间协调生长的机制。我们将研究一种提供血脑屏障的表面神经胶质细胞，神经膜下神经胶质细胞(SPG)。SPG生长以适应潜在的神经团块，同时通过增加倍体而不是分裂来保留血脑屏障的完整包膜。SPG倍体受神经元质量控制。包裹神经胶质细胞(WG)包裹周围神经系统中的轴突。它们的大小增加到50倍而不分裂，显然是通过增加倍性来实现的。我们将确定WG多倍化的作用和调控。我们的具体目标验证了三个假设：1)神经元质量通过增加神经元活性和/或机械张力促进SPG的倍性和大小增加；2)WG倍体的增加是生长所必需的，以允许延长轴突的包膜；以及3)周围神经中三个胶质层的大小是协调的。此外，我们将定义SPG和WG在正常条件下和当生长被相邻组织层改变时的转录本，作为一种识别指定这些胶质细胞功能的基因并响应来自其他细胞的提示而改变倍性的一种手段。这项提案的目标将通过使用果蝇遗传工具来标记细胞、抑制基因活性或过度表达具有精致发育特异性的基因来实现。

 DESCRIPTION (provided by applicant): The size of tissue layers is scaled during the development of organs. In the nervous system, the size of neurons and glia must be coordinated, particularly for glia such as Schwann cells and satellite cells that are in tight association with axons or neuronal cell bodies. Inappropriate growth of Schwann cells and satellite glia cells in response to nerve damage is linked to chronic pain. Despite its importance, little is understood about how neuronal and glial growth are coordinated. In Drosophila, at least two types of glia increase cell size by increasing DNA content (ploidy), a universal strategy to produce large cells throughout the plant and animal kingdoms. The ability to monitor glial cell size by measuring ploidy and to alter glial cell growth by changing ploidy provides additional experimental advantages to the powerful toolkit in Drosophila for analysis of development of the nervous system. We propose to exploit glial growth by ploidy in the Drosophila nervous system to define mechanisms that coordinate growth between glia and neurons in development. We will investigate one type of surface glia, the subperineurial glia (SPG), that provide the blood-brain barrier. SPG grow to accommodate the underlying neuronal mass while retaining an intact envelope for the blood-brain barrier by increasing ploidy rather than dividing. SPG ploidy is controlled by neuronal mass. The wrapping glia (WG) ensheath axons in the peripheral nervous system. They increase up to 50 fold in size without dividing, apparently by increasing ploidy. We will define the role and regulation of polyploidization of WG. Our specific aims test three hypotheses: 1) neuronal mass promotes ploidy and size increases for the SPG by increased neuronal activity and/or mechanical tension; 2) increased ploidy of the WG is necessary for growth to permit ensheathment of elongating axons; and 3) the size of the three glial layers in the peripheral nerves is coordinated. Additionally, we will define the transcriptomes of the SPG and WG under normal conditions and when growth is modified by adjacent tissue layers, as a means to identify genes that specify functions of these glia and alter ploidy in response to cues from other cells. The goals of this proposal will be achieved by using Drosophila genetic tools to label cells, inhibit gene activity, or overexpress genes with exquisite developmental specificity.