Glial control of neuron development and function

神经胶质细胞对神经元发育和功能的控制

• 批准号: 10063060
• 负责人: Shai Shaham
• 金额: $ 113.17万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10063060
• 关键词: Address; Afferent Neurons; Animals; Astrocytes; Biology; Brain; Bypass; Caenorhabditis elegans; Cell Death; Cell Fraction; Complement; Cues; Development; Excitatory Synapse; Goals; Hand; Human; Ions; Molecular; Nematoda; Nerve Degeneration; Nervous system structure; Neuroglia; Neuromuscular Junction; Neurons; Neurotransmitter Receptor; Neurotransmitters; Organ; Play; Radial; Sense Organs; Sensory; Shapes; Structure; Synapses; System; Testing; Ursidae Family; Vertebrates; functional plasticity; gliogenesis; in vivo; information processing; nervous system development; neuron development; programs; synaptic function; transcription factor

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-ensheathed, 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 differentiation 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 vertebrate 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 neurotransmitter 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 guided 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.

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、功能和信息处理做出贡献。神经胶质细胞构成脊椎动物神经系统中很大一部分细胞，并围绕神经元接受末梢形成孤立的隔室。大多数兴奋性突触是由胶质细胞包裹的，感觉神经元感受性终末和神经肌肉接头也是如此。我们对神经胶质细胞的理解仍然存在很大的差距。虽然已经探索了一些胶质细胞的发育特性，但调控星形胶质细胞或感觉器官胶质细胞分化的程序尚不清楚。神经胶质细胞如何形成和调节突触和其他神经元感受性末梢周围的隔室也不清楚。神经胶质细胞被提出用来调节神经元的活动，但其效应机制还没有得到充分的研究。最后，神经元结构和功能的可塑性可能在一定程度上受到神经胶质的控制，但细节尚不清楚。因此，关于神经胶质的功能及其潜在的分子程序仍有许多需要了解。在许多动物中，神经元与生俱来，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。因此，神经胶质操纵往往会导致神经元死亡。一个长期的目标是确定体内环境，以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。我们已经朝着这个目标迈出了重要的一步，开创了线虫作为一种简单和相关的系统来研究神经胶质细胞及其神经系统贡献。我们发现线虫具有神经胶质细胞，这些鞘感觉神经元接受末梢，与脊椎动物感觉器官中发现的神经胶质结构非常相似，以及包裹中枢神经系统，包裹在定义的突触周围。与脊椎动物星形胶质细胞类似，后者包含特定的CNS结构域，表达促进脊椎动物胶质形成的转录因子，表达离子和神经递质转运体、通道和神经递质受体。这些胶质细胞的发育与脊椎动物大脑发育中放射状胶质细胞到星形胶质细胞的发育过程有着惊人的相似之处。重要的是，在线虫中，神经元的存活不需要胶质细胞，但胶质细胞的操纵会导致神经元形状和功能的重大缺陷。因此，线虫为研究神经胶质细胞及其对神经系统的影响提供了一个独特的活体场所。在这里，我们的目标是研究神经胶质细胞生物学的三个相互关联的方面。(1)我们将确定星形胶质细胞如何发育和调节突触功能。(2)确定神经胶质细胞引导的脑组装。(3)我们将研究一种新的细胞死亡程序，类似于神经胶质细胞依赖的神经变性。在回答这些问题时，我们挑战了只有神经元才是所研究现象的基础的观点，并假设胶质细胞是完整的调节器。