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

基本信息

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
项目类别：
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

项目摘要

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促进神经系统发育、功能和信息处理。神经胶质细胞构成脊椎动物神经系统中的大部分细胞，并围绕神经元接受末梢形成隔离的区室。大多数兴奋性突触都被神经胶质包裹，感觉神经元接受末梢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重大差距。虽然已经探索了一些神经胶质细胞的发育规范，但控制星形胶质细胞或感觉器官神经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接受末梢周围的区室也尚不清楚。神经胶质细胞被认为可以调节神经元活动，但其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受到神经胶质细胞的控制，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还有很多东西有待了解。在许多动物中，神经元过量生成，最终的神经元补充部分取决于神经胶质和其他控制细胞死亡的分泌信号。因此，神经胶质细胞的操纵常常导致神经元死亡。一个长期目标是确定体内环境，用于研究胶质细胞-神经元相互作用，从而绕过神经元生存问题。我们向这一目标迈出了重要一步，开创了线虫线虫作为研究神经胶质细胞及其神经系统贡献的简便且相关的系统。我们发现秀丽隐杆线虫拥有神经胶质细胞，并且这些神经胶质细胞包裹着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高度相似，并且包裹着中枢神经系统，包裹着明确的突触。与脊椎动物星形胶质细胞一样，这些神经胶质细胞包含特定的 CNS 结构域，表达促进脊椎动物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到星形胶质细胞的发育转变有着惊人的相似之处。重要的是，在线虫中，神经元的生存不需要神经胶质细胞，但神经胶质细胞的操纵会导致神经元形状和功能的严重缺陷。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体内舞台。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育和调节突触功能。 (2)我们将确定神经胶质引导的大脑组装。 (3)我们将研究一种类似于神经胶质细胞依赖性神经变性的新细胞死亡程序。在解决这些问题时，我们挑战了只有神经元才是所研究现象的基础的观点，并假设神经胶质细胞是不可或缺的调节器。