Despite the essential roles of glia in neural development and function, our understanding of the genetic and molecular pathways underlying glial functions is still very limited. Most glial subtypes contribute to neuronal survival, and glil dysfunction is associated with most neurodegenerative conditions. In the vertebrate retina, the radial M?ller glia govern tissue homeostasis, neuroprotection and even regeneration, as the source of adult neural stem cells, but their reactive gliotic response to light damage leads to retinal degeneration. Therefore, elucidating the molecular pathways and mechanisms that mediate glia-neuron interactions, neuronal protection and support during visual system aging and disease is fundamental to guide clinical research. Detailed analysis of glial lineages in the Drosophila nervous system has revealed cells analogous to many vertebrate glial subtypes. Surprisingly, however, no intrinsic glial cell population has yet been defined in the Drosophila compound eye, a deeply studied visual system in which innumerable conserved biological pathways have been discovered. Here, combining cell-specific genetic knockdowns, transcriptomics and electrophysiological methods, we provide evidence that cone cells (CCs), a subset of cells in the fly eye known to secrete the corneal lens, also provide crucial homeostatic support functions that ensure and maintain proper photoreceptor function. Furthermore, we show that this glia-related support requires the evolutionarily conserved neural stem cell and gliogenic factor, Prospero (Pros, vertebrate Prox1).
In Aim 1, we propose to test the hypothesis that CCs serve glial support cell functions, assaying the extent to which CCs mediate protective functions characteristic of M?ller glia in the vertebrate retina.
In Aim 2, to identify genes involed in neuroprotection, we will define Pros-regulated networks in CCs that are critical for preventing light-induced photoreceptor degeneration in the adult eye. Combined, the completion of these studies would establish a new experimental paradigm and develop the necessary molecular, genetic, morphological and physiological tools to rapidly dissect gene regulatory networks underlying glia-dependent neuroprotection with the precision of Drosophila genetics.

Public Health Relevance

Glial cells cooperate with neurons to ensure the proper formation and function of the nervous system, and defects in glial function are associated with such nervous system disorders as Parkinson's, Alzheimer's, brain cancer, autism and blindness. However, how and why glia contributes to neuroprotection versus neurodegeneration in different contexts is incompletely understood. In this work, we propose to develop a new, genetically robust, yet inexpensive and simple experimental system that uses the fly eye as a model to rapidly define molecular networks controlling glial roles capable of preserving neuronal function and preventing neurodegeneration. Given the evolutionary conservation of visual system's molecular regulation, the data produced by our studies will guide future experimental and clinical research aimed at developing targeted tools for diagnostic and treatment options for diseases associated with glia, including vision loss.

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (BVS)
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Neuhold, Lisa
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Cincinnati Children's Hospital Medical Center
United States
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