Glia-neuron signaling in the healthy and diseased brain
Neurons are not alone in the nervous system. Glial cells constitute the majority of the cells in the human brain. Despite their abundance, we know surprisingly little about how glia develop or function in the mature nervous system. Understanding glial cell biology and neuron-glia interactions has become an important line of investigation contemporary neuroscience. Exciting recent work from the field has demonstrated central roles for this enigmatic cell type in neural circuit assembly, function, and plasticity. Moreover, glial cells appear to be primary responders to neuronal injury and neurodegenerative disease, but whether they are directly affected by disease, are responding to disease, or are in fact driving neuronal loss during disease remains unclear. Defining the precise roles that glia play will be a crucial step if we wish understand how the nervous system is assembled, functions to drive animal behavior, and is maintained in a healthy state for the life of an animal.
Our group uses the fruit fly Drosophila as a model to explore fundamental aspects of glial cell biology. The major advantages of the fly are its remarkable collection of molecular-genetic tools for the analysis of gene function, the depth of our understanding of the development, histology and function of the Drosophila nervous system, and the opportunity this system presents to perform forward genetic screens to identify molecules required for glia-neuron interactions in vivo. Some of our key areas of focus include the following:
1) How do you make an astrocyte, and what does it do? Astrocytes are the most abundant cell type in the mammalian brain. We made the recent exciting discovery that astrocytes are also present in the Drosophila brain and are now using the fly to explore how these cells develop, the roles they play in neural circuit formation, and how astrocytes modulate brain function and behavior.
2) How do glial cells recognize and dispose of neuronal debris? During normal development or after nervous system injury or disease, neuronal processes (axons, dendrites, and synapses) can degenerate and neuronal cell bodies often undergo apoptotic cell death. Glial cells are the primary cell type responsible for recognizing and clearing this neuronal debris. We are interested in understanding how neurons signal to glia to indicate debris is present and needs clearance, and the molecular basis of glial recognition and phagocytosis of neuronal debris.
3) How are long axons wrapped and supported by glia? Long axons in mammals in flies are surrounded, and often individually ensheathed, by glial processes. Such insulation is thought to be critical for enhanced nerve conduction velocity and trophic support of long axons that are some distance from the cell body. We are exploring the molecular basis of axonal ensheathment in Drosophila and the mechanisms by which surrounding glial cells promote the survival and function of the axons they ensheath.
4) How do axons undergo auto-destruction? Severed axons (and dendrites) degenerate after axotomy, but is this a passive wasting away or an active death process? We recently discovered that deletion of the dSarm/Sarm1 gene resulted in the long-term survival of the distal portions of severed axon in both flies and mice. This work provided direct evidence for the existence of a dSarm/Sarm1-dependent axon death signaling pathway. We are now using powerful molecular approaches in Drosophila to identify additional axon death genes, and exploring the role of axon death signaling in neuron loss during disease using both fly and mouse models of neurological disorders.