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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018132-06
Application #
8296269
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
2007-04-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
6
Fiscal Year
2012
Total Cost
$388,750
Indirect Cost
$138,750
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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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
Goldman, Daniel (2014) Müller glial cell reprogramming and retina regeneration. Nat Rev Neurosci 15:431-42
Powell, Curtis; Cornblath, Eli; Goldman, Daniel (2014) Zinc-binding domain-dependent, deaminase-independent actions of apolipoprotein B mRNA-editing enzyme, catalytic polypeptide 2 (Apobec2), mediate its effect on zebrafish retina regeneration. J Biol Chem 289:28924-41
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
Zhao, Xiao-Feng; Wan, Jin; Powell, Curtis et al. (2014) Leptin and IL-6 family cytokines synergize to stimulate Müller glia reprogramming and retina regeneration. Cell Rep 9:272-84
Powell, Curtis; Elsaeidi, Fairouz; Goldman, Daniel (2012) Injury-dependent Muller glia and ganglion cell reprogramming during tissue regeneration requires Apobec2a and Apobec2b. J Neurosci 32:1096-109
Wan, Jin; Ramachandran, Rajesh; Goldman, Daniel (2012) HB-EGF is necessary and sufficient for Muller glia dedifferentiation and retina regeneration. Dev Cell 22:334-47
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Ghiasvand, Noor M; Rudolph, Dellaney D; Mashayekhi, Mohammad et al. (2011) Deletion of a remote enhancer near ATOH7 disrupts retinal neurogenesis, causing NCRNA disease. Nat Neurosci 14:578-86

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