Ascl1a regulates Müller glia dedifferentiation and retinal regeneration through a Lin-28-dependent, let-7 microRNA signalling pathway

Müller glia in the zebrafish retina respond to retinal damage by re-entering the cell cycle, which generates large numbers of retinal progenitors that ultimately replace the lost neurons. In this study we compared the regenerative outcomes of adult zebrafish exposed to one round of phototoxic treatment with adult zebrafish exposed to six consecutive rounds of phototoxic treatment. We observed that Müller glia continued to re-enter the cell cycle to produce clusters of retinal progenitors in zebrafish exposed to multiple rounds of phototoxic light. Some abnormalities were noted, however. First, we found that retinas exposed to multiple rounds of damage exhibited a greater loss of photoreceptors at 36 hours of light damage than retinas that were exposed to their first round of light damage. In addition, we found that Müller glia appeared to have an increase in the acute gliotic response in retinas exposed to multiple rounds of light treatment. This was evidenced by cellular hypertrophy, changes in GFAP cellular localization, and transient increases in stat3 and gfap expression. Finally, following the sixth round of phototoxic lesion, we observed a significant increase in mis-localized HuC/D-positive amacrine and ganglion cells in the inner plexiform layer and outer retina, and a decreased number of regenerated blue cone photoreceptors. These data add to recent findings that retinal regeneration in adult zebrafish occurs concomitant with Müller glia reactivity and can result in the generation of aberrant neurons. These data are also the first to demonstrate that Müller glia appear to modify their phenotype in response to multiple rounds of phototoxic lesion, exhibiting an increase in acute gliosis while maintaining a remarkable capacity for long-term regeneration of photoreceptors.

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Gene regulatory networks controlling vertebrate retinal regeneration

Science ◽

10.1126/science.abb8598 ◽

2020 ◽

Vol 370 (6519) ◽

pp. eabb8598 ◽

Cited By ~ 3

Author(s):

Thanh Hoang ◽

Jie Wang ◽

Patrick Boyd ◽

Fang Wang ◽

Clayton Santiago ◽

...

Keyword(s):

Gene Regulatory Networks ◽

Gene Networks ◽

Regulatory Networks ◽

Chromatin Accessibility ◽

Specific Gene ◽

Muller Glia ◽

Müller Glia ◽

Retinal Regeneration ◽

Adult Mice ◽

Gene Regulatory

Injury induces retinal Müller glia of certain cold-blooded vertebrates, but not those of mammals, to regenerate neurons. To identify gene regulatory networks that reprogram Müller glia into progenitor cells, we profiled changes in gene expression and chromatin accessibility in Müller glia from zebrafish, chick, and mice in response to different stimuli. We identified evolutionarily conserved and species-specific gene networks controlling glial quiescence, reactivity, and neurogenesis. In zebrafish and chick, the transition from quiescence to reactivity is essential for retinal regeneration, whereas in mice, a dedicated network suppresses neurogenic competence and restores quiescence. Disruption of nuclear factor I transcription factors, which maintain and restore quiescence, induces Müller glia to proliferate and generate neurons in adult mice after injury. These findings may aid in designing therapies to restore retinal neurons lost to degenerative diseases.

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Dynamic miRNA expression patterns during retinal regeneration in zebrafish: Reduced dicer or miRNA expression suppresses proliferation of Müller Glia‐derived neuronal progenitor cells

Developmental Dynamics ◽

10.1002/dvdy.24188 ◽

2014 ◽

Vol 243 (12) ◽

pp. 1591-1605 ◽

Cited By ~ 20

Author(s):

Kamya Rajaram ◽

Rachel L. Harding ◽

Travis Bailey ◽

James G. Patton ◽

David R. Hyde

Keyword(s):

Progenitor Cells ◽

Mirna Expression ◽

Expression Patterns ◽

Muller Glia ◽

Müller Glia ◽

Retinal Regeneration ◽

Neuronal Progenitor Cells ◽

Neuronal Progenitor

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Characterization of Müller glia and neuronal progenitors during adult zebrafish retinal regeneration

Experimental Eye Research ◽

10.1016/j.exer.2008.07.009 ◽

2008 ◽

Vol 87 (5) ◽

pp. 433-444 ◽

Cited By ~ 98

Author(s):

Ryan Thummel ◽

Sean C. Kassen ◽

Jennifer M. Enright ◽

Craig M. Nelson ◽

Jacob E. Montgomery ◽

...

Keyword(s):

Muller Glia ◽

Müller Glia ◽

Retinal Regeneration ◽

Adult Zebrafish ◽

Neuronal Progenitors

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Inflammation Regulates the Multi-Step Process of Retinal Regeneration in Zebrafish

Cells ◽

10.3390/cells10040783 ◽

2021 ◽

Vol 10 (4) ◽

pp. 783

Author(s):

Mikiko Nagashima ◽

Peter F. Hitchcock

Keyword(s):

Cell Death ◽

Radial Glia ◽

Current Knowledge ◽

Muller Glia ◽

Müller Glia ◽

Retinal Regeneration ◽

Step Process ◽

Ability To Regenerate ◽

Activate Complex ◽

Almost All

The ability to regenerate tissues varies between species and between tissues within a species. Mammals have a limited ability to regenerate tissues, whereas zebrafish possess the ability to regenerate almost all tissues and organs, including fin, heart, kidney, brain, and retina. In the zebrafish brain, injury and cell death activate complex signaling networks that stimulate radial glia to reprogram into neural stem-like cells that repair the injury. In the retina, a popular model for investigating neuronal regeneration, Müller glia, radial glia unique to the retina, reprogram into stem-like cells and undergo a single asymmetric division to generate multi-potent retinal progenitors. Müller glia-derived progenitors then divide rapidly, numerically matching the magnitude of the cell death, and differentiate into the ablated neurons. Emerging evidence reveals that inflammation plays an essential role in this multi-step process of retinal regeneration. This review summarizes the current knowledge of the inflammatory events during retinal regeneration and highlights the mechanisms whereby inflammatory molecules regulate the quiescence and division of Müller glia, the proliferation of Müller glia-derived progenitors and the survival of regenerated neurons.

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Efficient stimulation of retinal regeneration from Müller glia in adult mice using combinations of proneural bHLH transcription factors

Cell Reports ◽

10.1016/j.celrep.2021.109857 ◽

2021 ◽

Vol 37 (3) ◽

pp. 109857

Author(s):

Levi Todd ◽

Marcus J. Hooper ◽

Alexandra K. Haugan ◽

Connor Finkbeiner ◽

Nikolas Jorstad ◽

...

Keyword(s):

Transcription Factors ◽

Muller Glia ◽

Müller Glia ◽

Retinal Regeneration ◽

Adult Mice ◽

Bhlh Transcription Factors ◽

Stimulation Of

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Antiviral Drug Ganciclovir Is a Potent Inhibitor of the Proliferation of Müller Glia–Derived Progenitors During Zebrafish Retinal Regeneration

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.15-18669 ◽

2016 ◽

Vol 57 (4) ◽

pp. 1991 ◽

Cited By ~ 3

Author(s):

Shuqiang Zhang ◽

Zhaoxia Mu ◽

Chunjiao He ◽

Minmin Zhou ◽

Dong Liu ◽

...

Keyword(s):

Potent Inhibitor ◽

Antiviral Drug ◽

Muller Glia ◽

Müller Glia ◽

Retinal Regeneration

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Transgenic expression of the proneural transcription factor Ascl1 in Müller glia stimulates retinal regeneration in young mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1510595112 ◽

2015 ◽

Vol 112 (44) ◽

pp. 13717-13722 ◽

Cited By ~ 120

Author(s):

Yumi Ueki ◽

Matthew S. Wilken ◽

Kristen E. Cox ◽

Laura Chipman ◽

Nikolas Jorstad ◽

...

Keyword(s):

Transcription Factor ◽

Bipolar Cells ◽

Muller Glia ◽

Müller Glia ◽

Retinal Regeneration ◽

Transgenic Expression ◽

Retinal Injury ◽

Young Mice

Müller glial cells are the source of retinal regeneration in fish and birds; although this process is efficient in fish, it is less so in birds and very limited in mammals. It has been proposed that factors necessary for providing neurogenic competence to Müller glia in fish and birds after retinal injury are not expressed in mammals. One such factor, the proneural transcription factor Ascl1, is necessary for retinal regeneration in fish but is not expressed after retinal damage in mice. We previously reported that forced expression of Ascl1 in vitro reprograms Müller glia to a neurogenic state. We now test whether forced expression of Ascl1 in mouse Müller glia in vivo stimulates their capacity for retinal regeneration. We find that transgenic expression of Ascl1 in adult Müller glia in undamaged retina does not overtly affect their phenotype; however, when the retina is damaged, the Ascl1-expressing glia initiate a response that resembles the early stages of retinal regeneration in zebrafish. The reaction to injury is even more pronounced in Müller glia in young mice, where the Ascl1-expressing Müller glia give rise to amacrine and bipolar cells and photoreceptors. DNaseI-seq analysis of the retina and Müller glia shows progressive reduction in accessibility of progenitor gene cis-regulatory regions consistent with the reduction in their reprogramming. These results show that at least one of the differences between mammal and fish Müller glia that bears on their difference in regenerative potential is the proneural transcription factor Ascl1.

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