scholarly journals miRNAs and Müller Glia Reprogramming During Retina Regeneration

2021 ◽  
Vol 8 ◽  
Author(s):  
Gregory J. Konar ◽  
Claire Ferguson ◽  
Zachary Flickinger ◽  
Matthew R. Kent ◽  
James G. Patton
Keyword(s):  
Chromatin Accessibility ◽  
Model Systems ◽  
Signaling Cascades ◽  
Small Subset ◽  
Muller Glia ◽  
Müller Glia ◽  
Key Factors ◽  
Genetic Pathways ◽  
Retina Regeneration ◽  
Gene Regulatory

The use of model systems that are capable of robust, spontaneous retina regeneration has allowed for the identification of genetic pathways and components that are required for retina regeneration. Complemented by mouse models in which retina regeneration can be induced after forced expression of key factors, altered chromatin accessibility, or inhibition of kinase/signaling cascades, a clearer picture of the key regulatory events that control retina regeneration is emerging. In all cases, Müller glia (MG) serve as an adult retinal stem cell that must be reprogrammed to allow for regeneration, with the end goal being to understand why regenerative pathways are blocked in mammals, but spontaneous in other vertebrates such as zebrafish. miRNAs have emerged as key gene regulatory molecules that control both development and regeneration in vertebrates. Here, we focus on a small subset of miRNAs that control MG reprogramming during retina regeneration and have the potential to serve as therapeutic targets for treatment of visual disorders and damage.

scholarly journals Gene regulatory networks controlling vertebrate retinal regeneration

Science ◽  
2020 ◽  
Vol 370 (6519) ◽  
pp. eabb8598 ◽  
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.

scholarly journals Cross-species transcriptomic and epigenomic analysis reveals key regulators of injury response and neuronal regeneration in vertebrate retinas

2019 ◽  
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 ◽  
Rna Seq ◽  
Adult Mice ◽  
Gene Regulatory

AbstractInjury induces retinal Müller glia of cold-blooded, but not mammalian, vertebrates to regenerate neurons. To identify gene regulatory networks that control neuronal reprogramming in retinal glia, we comprehensively profiled injury-dependent changes in gene expression and chromatin accessibility in Müller glia from zebrafish, chick and mice using bulk RNA-Seq and ATAC-Seq, as well as single-cell RNA-Seq. Cross-species integrative analysis of these data, together with functional validation, identified evolutionarily conserved and species-specific gene networks controlling glial quiescence, gliosis and neurogenesis. In zebrafish and chick, transition from the resting state to gliosis is essential for initiation of retinal regeneration, while in mice a dedicated network suppresses neurogenic competence and restores quiescence. Selective disruption of NFI family transcription factors, which maintain and restore quiescence, enables Müller glia to proliferate and generate neurons in adult mice following retinal injury. These findings may aid in the design of cell-based therapies aimed at restoring retinal neurons lost to degenerative disease.Summary sentenceThis study identifies gene regulatory networks controlling proliferative and neurogenic competence in retinal Müller glia.

scholarly journals Midkine in chick and mouse retinas: neuroprotection, glial reactivity and the formation of Müller glia-derived progenitor cells

2020 ◽  
Author(s):  
Warren A. Campbell ◽  
Amanda Fritsch-Kelleher ◽  
Isabella Palazzo ◽  
Thanh Hoang ◽  
Seth Blackshaw ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Neuronal Survival ◽  
Expression Patterns ◽  
Model Systems ◽  
Muller Glia ◽  
Heparin Binding ◽  
Müller Glia ◽  
Related Factors ◽  
Neuroprotective Effects ◽  
Dying Cells

AbstractRecent studies have shown that midkine (MDK), a basic heparin-binding growth factor, is involved in the development and regeneration of the zebrafish retina. However, very little is known about MDK in the retinas of warm-blooded vertebrates. We investigate the expression patterns of MDK and related factors, roles in neuronal survival, and influence upon the formation of Müller glia-derived progenitor cells (MGPCs) in chick and mouse model systems. By using single-cell RNA-sequencing, we find that MDK is upregulated during Müller glia (MG) maturation in chick development and when stimulated to reprogram into MGPCs after NMDA damage or FGF2/Insulin treatment. Interestingly, MDK is significantly up-regulated by MG in damaged chick retinas, but down-regulated by MG in damaged mouse retinas. In both chick and mouse retinas, exogenous MDK selectively up-regulates cFOS and pS6 (a readout of mTOR-signaling) in MG. In the chick, intraocular injections of MDK before injury is neuroprotective with an observed decrease in dying neurons and microglial reactivity, inducing fewer proliferating MGPCs. Blocking MDK signaling with Na3VO4 following blocks neuroprotective effects with an increase the number of dying cells and negates the pro-proliferative effects on MGPCs. Inhibitors of PP2A and Pak1 associated with MDK integrin β1 signaling had MG specific inhibitory effects on MGPC formation. In mice, MDK administration with NMDA damage drives a small but significant increase in MGPCs. We conclude that MDK expression is dynamically regulated in reactive Müller glia and during reprogramming into MGPCs. MDK acts to coordinate glial activity, neuronal survival, and may act in an autocrine manner to influence the re-programming of Müller glia into proliferating MGPCs.

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 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

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.

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