Mechanisms of Glial Interactions and Function at Neuronal Cell Bodies

项目摘要/摘要 中枢神经系统(CNS)的所有主要哺乳动物神经胶质亚型都与神经细胞直接接触 身体；然而，神经胶质细胞如何支持和与神经元SoMAS沟通的研究远远不够 突触或轴突的神经胶质相互作用。这个项目的首要目标是获得一种深刻的机械性 了解神经胶质细胞的发育、通讯和神经元胞体的功能，开始填写 这些关联如何调节中枢神经系统健康和功能障碍的差距。果蝇神经胶质细胞表现非凡 从形态、功能和分子方面衡量与许多哺乳动物神经胶质亚型的相似性 标准。其中包括皮质胶质细胞，这是一种形成花边状网络的神经胶质亚类，可单独包膜。 中枢神经系统中几乎每一个神经元胞体。我们最近开发了新的遗传工具来操纵基因功能 在果蝇皮质神经胶质细胞中具有显著的特异性，现在有了一个强大的系统来研究神经胶质细胞 体内神经元胞体的发育和神经元-神经胶质细胞的相互作用。除了调节神经元 健康和行为，皮质胶质细胞为神经元提供代谢支持，调节神经元离子和营养 平衡，吞噬神经元碎片，因此可以为询问多个脊椎动物神经胶质细胞提供信息 与神经元胞体相互作用。 我们先前证明，当皮质胶质细胞缺乏单一的分泌神经营养因子Spätzle 3(Spz3)时，它们 呈现球状外观，不再包裹神经元细胞体。Spz3和这些神经胶质细胞的丢失 相互作用导致广泛的神经系统功能障碍，包括增加神经细胞死亡，运动 周围健康的神经胶质细胞受损和异常生长。我们建议使用强大的体内基因 在果蝇中可用的工具，以及细胞和分子生物学、生物化学、 和成像，以阐明在活的、完整的神经细胞中维持神经元健康的神经胶质-胞体相互作用的机制 神经系统。具体地说，我们将剖析调节这一过程成熟和分配的机制。 神经营养因子维持神经元胞体内的神经胶质接触(目标1)，定义该神经营养因子如何信号转导其 支持胶质细胞形态、胞体相互作用和神经元健康的受体(目标2)，最后，我们将 确定当神经胶质-胞体信号和联系受损时，附近的神经胶质细胞如何进行补偿(目标3)。 这些发现将通过提供一个基础，开始揭示一个未被充分研究但却很重要的现象 为了阐明神经胶质细胞与神经元胞体相互作用的细胞和分子基础。 健康和患病的中枢神经系统。

PROJECT SUMMARY/ABSTRACT All major mammalian glial subtypes of the central nervous system (CNS) make direct contacts with neuronal cell bodies; however, how glia support and communicate with neuronal somas is vastly understudied compared to glial interactions at synapses or axons. The overarching goal of this project is to gain a deep mechanistic understanding of glial development, communication, and function at neuronal cell bodies to begin to fill in the gaps of how these associations regulate CNS health and dysfunction. Drosophila glia demonstrate remarkable similarity to a number of mammalian glial subtypes measured by morphological, functional, and molecular criteria. Among these is cortex glia, a glial subclass that forms a lace-like meshwork to individually ensheath nearly every neuronal cell body in the CNS. We recently developed new genetic tools to manipulate gene function with remarkable specificity in Drosophila cortex glia, and now have a powerful system in which to study glial cell development and neuron-glia interactions at neuronal cell bodies in vivo. In addition to regulating neuronal health and behavior, cortex glia provide metabolic support to neurons, regulate neuronal ion and nutrient balance, engulf neuronal debris, and can therefore inform the interrogation of multiple vertebrate glial cells that interact with neuronal cell bodies. We previously demonstrated that when cortex glia lack a single secreted neurotrophin, Spätzle 3 (Spz3), they take on a globular appearance and no longer wrap neuronal cell bodies. The loss of Spz3 and these glial-somal interactions leads to widespread nervous system dysfunction, including increased neuronal cell death, locomotor impairment, and aberrant growth of surrounding healthy glial cells. We propose to use powerful in vivo genetic tools available in Drosophila, along with a variety of techniques in cellular and molecular biology, biochemistry, and imaging to elucidate the mechanisms of glial-somal interactions that maintain neuronal health in a live, intact nervous system. Specifically, we will dissect the mechanisms that regulate the maturation and distribution of this neurotrophin to maintain glial contact at neuronal cell bodies (Aim 1), define how this neurotrophin signals to its receptor to support glial morphology, somal interactions, and neuronal health (Aim 2), and finally, we will determine how nearby glial cells compensate when glial-somal signaling and associations are impaired (Aim 3). These findings will begin to shed light on an understudied, yet important phenomenon by providing a foundation for elucidating the cellular and molecular underpinnings of glial interactions with neuronal cell bodies in the healthy and diseased CNS.