Glial control of neuron development and function

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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.