Mechanisms of Glial Interactions and Function at Neuronal Cell Bodies

项目概要/摘要 哺乳动物中枢神经系统（CNS）的所有主要胶质细胞亚型都与神经元细胞直接接触 然而，胶质细胞如何支持和沟通与神经元胞体是远远不足的研究相比， 神经胶质在突触或轴突上的相互作用。这个项目的首要目标是获得一个深刻的机械 了解神经胶质细胞的发育，通讯和功能在神经元细胞体开始，以填补 这些协会如何调节中枢神经系统的健康和功能障碍的差距。果蝇的神经胶质 通过形态学、功能和分子生物学测量， 的搜索.其中之一是皮质神经胶质，这是一个神经胶质亚类，形成一个花边状的网络， 中枢神经系统中几乎所有的神经元细胞体。我们最近开发了新的遗传工具来操纵基因功能 在果蝇皮层神经胶质细胞中具有显著的特异性，现已建立了一个研究神经胶质细胞的强有力的系统 发育和体内神经元细胞体中神经元-神经胶质相互作用。除了调节神经元 健康和行为，皮层神经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，因此可以告知询问多种脊椎动物神经胶质细胞， 与神经元细胞体相互作用。 我们以前证明，当皮质神经胶质细胞缺乏一种分泌的神经营养因子Spätzle 3（Spz 3）时， 呈现球形外观，不再包裹神经元细胞体。Spz 3和这些胶质细胞体的丢失 相互作用导致广泛的神经系统功能障碍，包括增加神经元细胞死亡，运动， 损伤和周围健康神经胶质细胞的异常生长。我们建议使用强大的体内遗传 果蝇中可用的工具，沿着细胞和分子生物学，生物化学， 和成像，以阐明神经胶质细胞相互作用的机制，维持神经元的健康，在一个活的，完整的 神经系统具体来说，我们将剖析调节这种成熟和分布的机制。 神经营养蛋白维持神经元细胞体的神经胶质接触（目的1），定义这种神经营养蛋白如何向其 受体支持神经胶质形态，体相互作用和神经元健康（目标2），最后，我们将 确定当神经胶质体信号传导和关联受损时，附近的神经胶质细胞如何补偿（目标3）。 这些发现将开始阐明一个未充分研究，但重要的现象，提供一个基础 用于阐明神经胶质细胞与神经元细胞体相互作用的细胞和分子基础， 健康和患病的CNS。

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.