Retinal degenerative diseases often lead to blindness due to lost neurons. A major goal of vision scientists is to restore these lost neurons. Due to their remarkable regenerative powers, zebrafish provide an ideal system for identifying strategies for restoring lost neurons in the retina. Although the zebrafish and mammalian retina are composed of similar cell types that are organized and function in a similar manner, they respond very differently to injury. Zebrafish respond to retinal damage by mounting a regenerative response that restores lost sight, while mammals do not. Key to the success of retina regeneration in zebrafish are Muller glia (MG) that respond to retinal damage by undergoing a reprogramming event that allows them to acquire properties of a stem cell. These reprogrammed MG are responsible for generating a multipotent proliferating population of retinal progenitors that regenerate all major retinal cell types. We propose that an understanding of the mechanisms by which MG reprogram to a retinal stem cell will help identify strategies for stimulating mammalian MG to undergo a similar transformation and repair a damaged retina. This proposal focuses on identifying these mechanisms with an emphasis on secreted factors regulating MG reprogramming and the gene expression programs that drive multipotency. It is anticipated that these studies will lead to novel strategies for inducing MG dedifferentiation and retina regeneration in mammals which may facilitate repairing a damaged or diseased human retina.

Public Health Relevance

Human retinal diseases and injury often lead to irreparable blindness due to lost neurons. Muller glia represents a potential source of retinal stem cells for repair of the damaged and diseased human retina. Our research takes advantage of the robust regenerative powers of zebrafish Muller glia to help identify strategies for stimulating mammalian Muller glia to reprogram to a retinal stem cell so it can contribute to repair of the diseased human retina.

National Institute of Health (NIH)
National Eye Institute (NEI)
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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
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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
Wan, Jin; Goldman, Daniel (2017) Opposing Actions of Fgf8a on Notch Signaling Distinguish Two Muller Glial Cell Populations that Contribute to Retina Growth and Regeneration. Cell Rep 19:849-862
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