Despite structural and functional similarities between the teleost and mammalian retina, disease or injury of the mammalian retina leads to irreparable vision loss, while the injured teleost retina mounts a regenerative response that restores lost sight. Key to successful regeneration is Muller glia (MG), which dedifferentiate and generate retinal progenitors that can regenerate all major retinal cell types. In contrast, mammalian MG responds to retinal injury by reactive gliosis that is accompanied by hypertrophy;rarely do these cells re-enter the cell cycle and regenerate new neurons. These data suggest that a key difference between the regenerative responses of fish and mammals is the ability of MG to dedifferentiate following retinal injury. We propose that an understanding of the mechanisms by which MG dedifferentiate and generate a proliferating population of retinal progenitors will suggest novel strategies for stimulating this process in mammalian MG. Because zebra fish mount a robust regenerative response following retinal injury, they provide a useful model system for uncovering these mechanisms. This proposal focuses on uncovering secreted signals and receptors that stimulate MG dedifferentiation, mechanisms by which these signals are transmitted to the genome and mechanisms underlying proliferation of MG-derived progenitors. In addition, new zebra fish models have been created to test whether ablation of any retinal cell type is sufficient to induce MG dedifferentiation and retina regeneration and if any cells can compensate for loss of MG during retina regeneration. These studies should lead to novel strategies for inducing MG dedifferentiation and retina regeneration in mammals which can be applied to repairing a damaged or diseased human retina.

Public Health Relevance

Human retinal diseases and injury often lead to irreparable blindness. Muller glia represents a potential source of retinal stem cells for repair of the damaged and diseased human retina. Uncovering the mechanisms underlying MG dedifferentiation in zebra fish may suggest novel strategies for inducing this process in humans and thus lead to repair of damaged and diseased human retinas.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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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
Powell, Curtis; Cornblath, Eli; Elsaeidi, Fairouz et al. (2016) Zebrafish Müller glia-derived progenitors are multipotent, exhibit proliferative biases and regenerate excess neurons. Sci Rep 6:24851
Wan, Jin; Goldman, Daniel (2016) Retina regeneration in zebrafish. Curr Opin Genet Dev 40:41-47
Zhang, Shuqiang; Mu, Zhaoxia; He, Chunjiao et al. (2016) Antiviral Drug Ganciclovir Is a Potent Inhibitor of the Proliferation of Müller Glia-Derived Progenitors During Zebrafish Retinal Regeneration. Invest Ophthalmol Vis Sci 57:1991-2000
Goldman, Daniel (2014) Regeneration, morphogenesis and self-organization. Development 141:2745-9
Zhao, Xiao-Feng; Goldman, Daniel (2014) A new transgenic line reporting pStat3 signaling in glia. Zebrafish 11:588-9
Elsaeidi, Fairouz; Bemben, Michael A; Zhao, Xiao-Feng et al. (2014) Jak/Stat signaling stimulates zebrafish optic nerve regeneration and overcomes the inhibitory actions of Socs3 and Sfpq. J Neurosci 34:2632-44
Skaggs, Kaia; Goldman, Daniel; Parent, Jack M (2014) Excitotoxic brain injury in adult zebrafish stimulates neurogenesis and long-distance neuronal integration. Glia 62:2061-79

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