Glial Control of Neuron Development and Function - Administrative Supplement

我们的长期目标是了解神经胶质细胞如何对神经系统发育、功能和 信息处理。神经胶质细胞构成脊椎动物神经系统及其周围细胞的很大一部分 神经元的感受性末端形成孤立的隔室。大多数兴奋性突触是由神经胶质包被的， 是感觉神经元的感受性末梢和神经肌肉接头。我们在认识上仍然存在重大差距 神经胶质细胞。虽然已经探索了一些胶质细胞的发育规范，但管理星形胶质细胞或 感觉器官胶质细胞分化尚不清楚。神经胶质细胞如何形成和调节突触周围的隔室 其他神经元的感受性末梢也不是很清楚。神经胶质细胞被认为可以调节神经元 然而，效应器的机制还没有得到充分的探索。最后，神经元的结构和功能可塑性 可能在一定程度上受到了滑稽的控制，但细节尚不清楚。因此，仍有许多事情需要了解。 神经胶质功能及其潜在的分子程序。在许多动物中，神经元与生俱来，而 最终的神经元补体在一定程度上是由控制细胞死亡的神经胶质和其他分泌信号决定的。神经胶质 因此，操纵往往会导致神经元死亡。一个长期的目标是在活体环境中识别 用于研究绕过神经元生存问题的神经胶质细胞与神经元的相互作用。我们已经迈出了重要的一步 为了实现这一目标，通过开创线虫线虫作为一种简单和相关的系统来研究胶质细胞和 他们的神经系统贡献。我们发现线虫有神经胶质细胞，而这些神经鞘 感觉神经元感受性末梢，与脊椎动物感觉器官中的神经胶质结构高度相似，如 以及包裹中枢神经系统，包裹在已定义的突触周围。就像脊椎动物的星形胶质细胞，后者是胶质细胞， 包含特定的CNS结构域，表达促进脊椎动物胶质形成的转录因子，以及 表达离子和神经递质转运体、通道和神经递质受体。的发展。 这些胶质细胞与脊椎动物脑内放射状胶质细胞向星形胶质细胞的发育转变有着惊人的相似之处。 发展。重要的是，在线虫中，神经元的生存不需要胶质细胞，但胶质细胞的操纵会导致 神经元形态和功能的严重缺陷。因此，线虫提供了一个独特的体内研究胶质细胞和 它们对神经系统的影响。在这里，我们旨在研究胶质细胞神经元的三个相互关联的方面。 生物学。(1)我们将确定星形胶质细胞如何发育和调节突触功能。(2)我们会决定 神经胶质引导大脑组装。(3)我们将研究一种类似于神经胶质细胞依赖的新的细胞死亡程序 神经退行性变。在回答这些问题时，我们挑战了只有神经元才是 正在研究中的现象，并假设神经胶质细胞是整合的调节器。

Our long-term goal is to understand how glia contribute to nervous system development, function, and information processing. Glia constitute a large fraction of cells in the vertebrate nervous system and surround neuronal receptive endings to form isolated compartments. Most excitatory synapses are glia-ensheated, as are sensory-neuron receptive endings and neuromuscular junctions. Major gaps remain in our understanding of glia. While developmental specification of some glia has been explored, programs governing astrocyte or sensory organ glia differentation are not clear. How glia form and regulate compartments around synapses and other neuronal receptive endings is also not understood. Glia have been proposed to regulate neuronal activity, yet the effector mechanisms are not fully explored. Finally, neuron structural and functional plasticity may, in part, be under glial control, yet the details are not at hand. Thus, much remains to be learned about glial functions and their underlying molecular programs. In many animals, neurons are born in excess, and the final neuronal complement is determined in part by glial and other secreted cues controlling cell death. Glial manipulation, thus, often leads to neuronal demise. A long-standing goal has been to identify in vivo settings for studying glia-neuron interactions that bypass the neuron-survival problem. We have taken a major step towards this goal by pioneering the nematode C. elegans as a facile and relevant system for studying glia and their nervous system contributions. We showed that C. elegans possess glia, and that these ensheath sensory-neuron receptive endings, highly resembling glial structures found in vertebrates sense organs, as well as envelop the CNS, wrapping around defined synapses. Like vertebrate astrocytes, these latter glia tile, subsuming specific CNS domains, express transcription factors promoting gliogenesis in vertebrates, and express ion and neurotrasmitter transporters, channels, and neurotransmitter receptors. The development of these glia bears uncanny similarities to the radial glia-to-astrocyte developmental transition in vertebrate brain development. Importantly, in C. elegans, neuron survival does not require glia, but glia manipulation results in major deficits in neuron shape and function. C. elegans therefore offers a unique in vivo arena to study glia and their effects on the nervous system. Here we aim to investigate three interrelated aspects of glia-neuron biology. (1) We will determine how astrocytic glia develop and regulate synaptic function. (2) We will determine glia guide brain assembly. (3) We will study a new cell death program resembling glia-dependent neurodegeneration. In addressing these questions we challenge the view that only neurons underlie the phenomena under study, and posit that glia are integral regulators.