scholarly journals Oct4 mediates Müller glia reprogramming and cell cycle exit during retina regeneration in zebrafish

2019 ◽  
Vol 2 (5) ◽  
pp. e201900548 ◽  
Author(s):  
Poonam Sharma ◽  
Shivangi Gupta ◽  
Mansi Chaudhary ◽  
Soumitra Mitra ◽  
Bindia Chawla ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cellular Reprogramming ◽  
Muller Glia ◽  
Cell Cycle Exit ◽  
Müller Glia ◽  
Nucleosome Remodeling ◽  
Retina Regeneration ◽  
Inducing Factors ◽  
Transcription Factor 4 ◽  
Factor Governing

Octamer-binding transcription factor 4 (Oct4, also known as Pou5F3) is an essential pluripotency-inducing factor, governing a plethora of biological functions during cellular reprogramming. Retina regeneration in zebrafish involves reprogramming of Müller glia (MG) into a proliferating population of progenitors (MGPCs) with stem cell–like characteristics, along with up-regulation of pluripotency-inducing factors. However, the significance of Oct4 during retina regeneration remains elusive. In this study, we show an early panretinal induction of Oct4, which is essential for MG reprogramming through the regulation of several regeneration-associated factors such as Ascl1a, Lin28a, Sox2, Zeb, E-cadherin, and various miRNAs, namely, let-7a, miR-200a/miR-200b, and miR-143/miR-145. We also show the crucial roles played by Oct4 during cell cycle exit of MGPCs in collaboration with members of nucleosome remodeling and deacetylase complex such as Hdac1. Notably, Oct4 regulates Tgf-β signaling negatively during MG reprogramming, and positively to cause cycle exit of MGPCs. Our study reveals unique mechanistic involvement of Oct4, during MG reprogramming and cell cycle exit in zebrafish, which may also account for the inefficient retina regeneration in mammals.

scholarly journals Characterization of retinal regeneration in adult zebrafish following multiple rounds of phototoxic lesion

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5646 ◽  
Author(s):  
Alexandra H. Ranski ◽  
Ashley C. Kramer ◽  
Gregory W. Morgan ◽  
Jennifer L. Perez ◽  
Ryan Thummel
Keyword(s):  
Cell Cycle ◽  
Cellular Localization ◽  
Ganglion Cells ◽  
Plexiform Layer ◽  
Inner Plexiform Layer ◽  
Muller Glia ◽  
Müller Glia ◽  
Light Damage ◽  
Retinal Regeneration ◽  
Adult Zebrafish

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.

scholarly journals Midkine-a is required for cell cycle progression of Müller glia during neuronal regeneration

2019 ◽  
Author(s):  
Mikiko Nagashima ◽  
Travis S. D’Cruz ◽  
Doneen Hesse ◽  
Christopher J. Sifuentes ◽  
Pamela A. Raymond ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Growth Factor ◽  
Cell Cycle Progression ◽  
Muller Glia ◽  
Neuronal Regeneration ◽  
Müller Glia ◽  
Cycle Progression ◽  
Neuronal Stem Cells ◽  
Cell Cycle Genes

SummaryIn zebrafish, Müller glia function as intrinsic retinal stem cells that can regenerate ablated neurons. Understanding the mechanisms governing neuronal stem cells may provide clues to regenerate neurons in mammals. We report that in Müller glia the cytokine/growth factor, Midkine-a, functions as a core autocrine regulator of the cell cycle. Utilizing midkine-a mutants, we determined that Midkine-a regulates elements of an Id2a-retinoblastoma network in reprogrammed Müller glia that controls the expression of cell cycle genes and is required for transition from G1 to S phases of the cell cycle. In mutants, Müller glia that fail to divide undergo reactive gliosis, a pathological hallmark of Müller glia in mammals. Finally, we show that activation of the Midkine-a receptor, ALK, is required for Müller glia proliferation. These data provide mechanistic insights into Müller glia stem cells in the vertebrate retina and suggest avenues for eliciting neuronal regeneration in mammals.

Pax6-positive müller glia cells express cell cycle markers but do not proliferate after photoreceptor injury in the mouse retina

Glia ◽  
2011 ◽  
Vol 59 (7) ◽  
pp. 1033-1046 ◽  
Author(s):  
Sandrine Joly ◽  
Vincent Pernet ◽  
Marijana Samardzija ◽  
Christian Grimm
Keyword(s):  
Cell Cycle ◽  
Mouse Retina ◽  
Muller Glia ◽  
Müller Glia ◽  
Glia Cells ◽  
Express Cell

scholarly journals Tgfb3 collaborates with PP2A and notch signaling pathways to inhibit retina regeneration

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Mi-Sun Lee ◽  
Jin Wan ◽  
Daniel Goldman
Keyword(s):  
Notch Signaling ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Neuronal Degeneration ◽  
Muller Glia ◽  
Müller Glia ◽  
Retina Regeneration ◽  
Retinal Injury ◽  
Multipotent Progenitors ◽  
Tgfb Signaling

Neuronal degeneration in the zebrafish retina stimulates Müller glia (MG) to proliferate and generate multipotent progenitors for retinal repair. Controlling this proliferation is critical to successful regeneration. Previous studies reported that retinal injury stimulates pSmad3 signaling in injury-responsive MG. Contrary to these findings, we report pSmad3 expression is restricted to quiescent MG and suppressed in injury-responsive MG. Our data indicates that Tgfb3 is the ligand responsible for regulating pSmad3 expression. Remarkably, although overexpression of either Tgfb1b or Tgfb3 can stimulate pSmad3 expression in the injured retina, only Tgfb3 inhibits injury-dependent MG proliferation; suggesting the involvement of a non-canonical Tgfb signaling pathway. Furthermore, inhibition of Alk5, PP2A or Notch signaling rescues MG proliferation in Tgfb3 overexpressing zebrafish. Finally, we report that this Tgfb3 signaling pathway is active in zebrafish MG, but not those in mice, which may contribute to the different regenerative capabilities of MG from fish and mammals.

scholarly journals Histone Deacetylase-Mediated Müller Glia Reprogramming through Her4.1-Lin28a Axis Is Essential for Retina Regeneration in Zebrafish

iScience ◽  
2018 ◽  
Vol 7 ◽  
pp. 68-84 ◽  
Author(s):  
Soumitra Mitra ◽  
Poonam Sharma ◽  
Simran Kaur ◽  
Mohammad Anwar Khursheed ◽  
Shivangi Gupta ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Muller Glia ◽  
Müller Glia ◽  
Retina Regeneration

scholarly journals Midkine-a Is Required for Cell Cycle Progression of Müller Glia during Neuronal Regeneration in the Vertebrate Retina

2019 ◽  
Vol 40 (6) ◽  
pp. 1232-1247 ◽  
Author(s):  
Mikiko Nagashima ◽  
Travis S. D'Cruz ◽  
Antoinette E. Danku ◽  
Doneen Hesse ◽  
Christopher Sifuentes ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Muller Glia ◽  
Neuronal Regeneration ◽  
Müller Glia ◽  
Cycle Progression ◽  
Vertebrate Retina

scholarly journals Leptin and IL-6 Family Cytokines Synergize to Stimulate Müller Glia Reprogramming and Retina Regeneration

Cell Reports ◽  
2014 ◽  
Vol 9 (1) ◽  
pp. 272-284 ◽  
Author(s):  
Xiao-Feng Zhao ◽  
Jin Wan ◽  
Curtis Powell ◽  
Rajesh Ramachandran ◽  
Martin G. Myers ◽  
...  
Keyword(s):  
Muller Glia ◽  
Müller Glia ◽  
Retina Regeneration
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