Glial control of neuron development and function

我们的长期目标是了解神经胶质细胞如何促进神经系统的发育、功能和信息处理。神经胶质细胞是脊椎动物神经系统中很大一部分细胞，围绕着神经元接受末梢形成孤立的隔室。大多数兴奋性突触都是神经胶质包裹的，感觉神经元的接受末梢和神经肌肉连接处也是如此。我们对神经胶质细胞的理解仍有很大的差距。虽然一些胶质细胞的发育特征已被探索，但星形胶质细胞或感觉器官胶质细胞分化的调控程序尚不清楚。神经胶质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不清楚。神经胶质细胞被认为具有调节神经元活动的作用，但其作用机制尚未得到充分探讨。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，还有许多有待了解的地方。在许多动物中，神经元出生时数量过多，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信号决定。因此，神经胶质的操纵常常导致神经元的死亡。一个长期的目标是确定体内环境来研究神经胶质-神经元相互作用，绕过神经元存活问题。我们已经朝着这个目标迈出了重要的一步，率先将秀丽隐杆线虫作为研究神经胶质及其神经系统贡献的一个简单而相关的系统。我们发现秀丽隐杆线虫拥有神经胶质，这些包膜感觉神经元接受末梢，高度类似于脊椎动物感觉器官中的神经胶质结构，并包裹着中枢神经系统，包裹着确定的突触。像脊椎动物的星形胶质细胞一样，这些胶质细胞包含特定的中枢神经系统结构域，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脑发育中的放射状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，在秀丽隐杆线虫中，神经元的存活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重大缺陷。因此秀丽隐杆线虫提供了一个独特的在体内研究神经胶质及其对神经系统的影响的舞台。在这里，我们的目的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脑组装。(3)我们将研究一种类似于胶质依赖性神经变性的新的细胞死亡程序。在解决这些问题时，我们挑战了只有神经元是所研究现象的基础的观点，并假设神经胶质是完整的调节器。

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-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.