Blinding eye diseases are among the most feared disabilities afflicting the human population. Macular degeneration and glaucoma are the leading causes of blindness in the USA. These diseases result from neurodegeneration. Although a number of strategies for restoring sight to the blind are being pursued, a regenerative one may be most ideal. Unfortunately mammals do not regenerate their CNS. However, hope comes from zebrafish that posess remarkable regenerative powers and can regenerate a damaged retina. The zebrafish retina shares structure and function with the mammalian retina and therefore, is an ideal system for studying retina regeneration. Key to the success of retina regeneration in zebrafish are Muller glia (MG) that respond to retinal damage by adopting properties of a stem cell that allows them to divide and generate progenitors for retinal repair. It appears that fish MG are more plastic than their mammalian counterparts and this plasticity allows them to acquire a stem cell-like state in response to retinal damage. This plasticity may be influenced by intrinsic mechanisms and also the enviroment MG reside in. Our studies investigates interactions between MG and their environment and how this impacts their quiescence and proliferation. In addition, MG may represent a heterogenous population of which some are more prone to participate in retinal repair than others. Our studies investigate MG heterogeneity and its impact on retina growth and regeneration. Finally, although the ability of zebrafish MG to regenerate neurons is well documented, little is known about the integration and function of these regenerated neurons in the retinal circuitry. Our studies will investigate regenerated neuron integration into preexisting visual circuits and their participation in phototransduction. These studies will not only further our understanding of MG plasticity and neuronal regeneration in zebrafish, but will also suggest new strategies for stimulating retina regeneration in mammals.

Public Health Relevance

Human retinal diseases and injury often lead to irreparable blindness due to lost neurons. Muller glia represent a potential source of retinal stem cells for repair of the damaged and diseased human retina. Zebrafish Muller glia exhibit an ability to acquire stem cell properties. Our research aims to understand how zebrafish Muller glia attain these stem cell characteristics and regenerates neurons. It is anticipated that this information will help design strategies for stimulating mammalian Muller glia to acquire stem cell properties so they can be used for retinal repair.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology of the Visual System Study Section (BVS)
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Greenwell, Thomas
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Elsaeidi, Fairouz; Macpherson, Peter; Mills, Elizabeth A et al. (2018) Notch Suppression Collaborates with Ascl1 and Lin28 to Unleash a Regenerative Response in Fish Retina, But Not in Mice. J Neurosci 38:2246-2261
Mills, Elizabeth A; Goldman, Daniel (2017) The Regulation of Notch Signaling in Retinal Development and Regeneration. Curr Pathobiol Rep 5:323-331
Goldman, Daniel (2014) Regeneration, morphogenesis and self-organization. Development 141:2745-9