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胶质细胞如何促进神经系统发育，功能和信息处理。神经胶质构成脊椎动物神经系统中的大部分细胞，并且包围神经元感受性末梢以形成隔离的隔室。大多数兴奋性突触都是胶质鞘，感觉神经元的感受性末梢和神经肌肉接头也是如此。我们对神经胶质的理解仍然存在重大差距。虽然一些神经胶质细胞的发育规格已被探索，程序管理星形胶质细胞或感觉器官神经胶质细胞分化尚不清楚。胶质细胞如何形成和调节突触和其他神经元接受末梢周围的隔室也尚不清楚。胶质细胞已被提出来调节神经元的活动，但效应机制尚未完全探讨。最后，神经元的结构和功能可塑性可能在一定程度上受到神经胶质的控制，但细节还不清楚。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的。在许多动物中，神经元是过量产生的，并且最终的神经元补充部分地由控制细胞死亡的神经胶质和其他分泌的线索决定。因此，神经胶质的操纵常常导致神经元的死亡。一个长期的目标一直是确定在体内环境研究胶质神经元的相互作用，绕过神经元的生存问题。我们已经朝着这个目标迈出了重要的一步，开创了线虫C。elegans作为研究神经胶质细胞及其神经系统贡献的一个简单和相关的系统。我们证明了C.线虫具有神经胶质，并且这些有鞘的感觉神经元感受性末梢，高度类似于脊椎动物感觉器官中发现的神经胶质结构，以及包裹CNS，包裹在限定的突触周围。与脊椎动物星形胶质细胞一样，后者的神经胶质细胞包含特定的CNS结构域，表达促进脊椎动物神经胶质生成的转录因子，并表达离子和神经递质转运蛋白、通道和神经递质受体。这些神经胶质细胞的发育与脊椎动物大脑发育中放射状神经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。重要的是，在C。神经元存活不需要神经胶质，但神经胶质操纵导致神经元形状和功能的主要缺陷。C.因此，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，我们的目标是研究胶质神经元生物学的三个相互关联的方面。(1)我们将确定星形胶质细胞如何发展和调节突触功能。(2)我们将确定神经胶质引导的大脑组装。(3)我们将研究一种新的细胞死亡程序，类似于胶质依赖性神经变性。在解决这些问题，我们挑战的观点，只有神经元基础的现象正在研究中，并重申，神经胶质细胞是不可或缺的监管机构。