Glial Control of Neuron Development and Function

神经胶质对神经元发育和功能的控制

• 批准号: 10528452
• 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/10528452
• 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; Learning; Molecular; Nematoda; Nerve Degeneration; Nervous System; Neuroglia; Neuromuscular Junction; Neurons; Neurotransmitter Receptor; Neurotransmitters; Organ; Play; Radial; Sense Organs; Sensory; Shapes; Specific qualifier value; Structure; Synapses; System; Testing; Vertebrates; functional plasticity; gliogenesis; in vivo; information processing; nervous system development; neuron development; neuronal survival; 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如何为神经系统的发展，功能和信息处理做出贡献。神经胶质在脊椎动物神经系统中构成了很大一部分细胞，并围绕神经元接受结束，形成孤立的隔室。大多数兴奋性突触都是神经胶质的，感觉 - 神经元的接受结尾和神经肌肉连接。我们对神经胶质的理解仍然存在主要差距。尽管已经探索了某些神经胶质的发育规范，但管理星形胶质细胞或感觉器官胶质分化的程序尚不清楚。尚不清楚神经胶质在突触和其他神经元接受结局周围的形成和调节隔室。已经提出了神经胶质来调节神经元活性，但效应机制尚未得到充分探索。最后，神经元的结构和功能可塑性可能部分地受到神经胶质控制，但细节却没有。因此，关于神经胶质功能及其潜在的分子程序还有很多待了解。在许多动物中，神经元出生过多，最终的神经元补体部分由神经胶质和其他控制细胞死亡的分泌提示确定。因此，神经胶质操纵通常会导致神经元灭亡。一个长期的目标是确定研究绕过神经元生存问题的神经胶质神经元相互作用的体内环境。我们通过开创了线虫秀丽隐杆线虫作为研究神经胶质及其神经系统贡献的轻松且相关的系统，从而朝着这一目标迈出了重要一步。我们表明秀丽隐杆线虫具有神经胶质，并且这些感官 - 神经元的接受结局，在脊椎动物感官器官中发现的高度相似的神经胶质结构，以及包裹CNS，围绕定义的突触包裹。像脊椎动物的星形胶质细胞一样，这些后一种神经胶质瓷砖，包含特定的CNS结构域，促进脊椎动物的神经胶质发生的表达转录因子，以及表达离子和神经递质转运蛋白转运蛋白，通道和神经递质受体。这些神经胶质的发育与脊椎动物脑发育中的径向神经胶质到胃细胞发育过渡具有不可思议的相似性。重要的是，在秀丽隐杆线虫中，神经元的存活不需要神经胶质，但是神经胶质的操作会导致神经元形状和功能的主要缺陷。因此，秀丽隐杆线虫提供了一个独特的体内竞技场来研究神经胶质及其对神经系统的影响。在这里，我们旨在研究胶质神经元生物学的三个相互关联的方面。 （1）我们将确定星形细胞胶质胶质的发展和调节突触功能。 （2）我们将确定胶质引导的大脑组件。 （3）我们将研究一个类似于神经胶质神经变性的新细胞死亡程序。在解决这些问题时，我们挑战了所研究现象的基础的观点，并认为神经胶质是不可或缺的调节剂。