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

Todd, Levi; Hooper, Marcus; Haugan, Alexandra K.; Finkbeiner, Connor; Jorstad, Nikolas L.; Radulovich, Nicholas; Wong, Claire K.; Donaldson, Phoebe C.; Jenkins, Wesley; Chen, Qiang; Rieke, Fred; Reh, Thomas A.

doi:10.1016/j.celrep.2021.109857

Cited by 111 publications

(121 citation statements)

References 48 publications

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“…Furthermore, diversifying the combination of neurogenic bHLH TFs enhances Müller glia trans-differentiation and neurogenesis in vivo. Müller glia co-expressing the bHLH TFs Atoh1 and Ascl1 give rise to bipolar and amacrine cells and immature retinal ganglion cell-like cells in the absence of injury, although cell bodies fail to migrate to the ganglion cell layer and the cells have only small axonal processes [ 320 ].…”

Section: Tackling the Epigenetic Contribution To Ocular Diseases For ...mentioning

confidence: 99%

Deciphering the Retinal Epigenome during Development, Disease and Reprogramming: Advancements, Challenges and Perspectives

Zibetti

2022

Cells

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Retinal neurogenesis is driven by concerted actions of transcription factors, some of which are expressed in a continuum and across several cell subtypes throughout development. While seemingly redundant, many factors diversify their regulatory outcome on gene expression, by coordinating variations in chromatin landscapes to drive divergent retinal specification programs. Recent studies have furthered the understanding of the epigenetic contribution to the progression of age-related macular degeneration, a leading cause of blindness in the elderly. The knowledge of the epigenomic mechanisms that control the acquisition and stabilization of retinal cell fates and are evoked upon damage, holds the potential for the treatment of retinal degeneration. Herein, this review presents the state-of-the-art approaches to investigate the retinal epigenome during development, disease, and reprogramming. A pipeline is then reviewed to functionally interrogate the epigenetic and transcriptional networks underlying cell fate specification, relying on a truly unbiased screening of open chromatin states. The related work proposes an inferential model to identify gene regulatory networks, features the first footprinting analysis and the first tentative, systematic query of candidate pioneer factors in the retina ever conducted in any model organism, leading to the identification of previously uncharacterized master regulators of retinal cell identity, such as the nuclear factor I, NFI. This pipeline is virtually applicable to the study of genetic programs and candidate pioneer factors in any developmental context. Finally, challenges and limitations intrinsic to the current next-generation sequencing techniques are discussed, as well as recent advances in super-resolution imaging, enabling spatio-temporal resolution of the genome.

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Section: Tackling the Epigenetic Contribution To Ocular Diseases For ...mentioning

confidence: 99%

Deciphering the Retinal Epigenome during Development, Disease and Reprogramming: Advancements, Challenges and Perspectives

Zibetti

2022

Cells

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“…In contrast, mammalian Müller glia enter a gliotic state in response to retinal injury and fail to enter a regenerative state. However, with certain genetic and pharmacological manipulations, including those of microglia, mammalian Müller glia may gain some capacity for neuronal regeneration (Jorstad et al, 2017; Rueda et al, 2019; Todd et al, 2020; Todd et al, 2021). Thus, Müller glia responses, and Müller glia‐microglia cross talk, are likely key to shaping/influencing the outcome after retinal injury, though the differences in zebrafish versus mammalian responses are still not well understood.…”

Section: Introductionmentioning

confidence: 99%

Compensatory engulfment and Müller glia reactivity in the absence of microglia

Thiel

Blume

Mitchell

2022

Glia

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Microglia are known for important phagocytic functions in the vertebrate retina. Reports also suggest that Müller glia have phagocytic capacity, though the relative levels and contexts in which this occurs remain to be thoroughly examined. Here, we investigate Müller glial engulfment of dying cells in the developing zebrafish retina in the presence and absence of microglia, using a genetic mutant in which microglia do not develop. We show that in normal conditions clearance of dying cells is dominated by microglia; however, Müller glia do have a limited clearance role. In retinas lacking intact microglial populations, we found a striking increase in the engulfment load assumed by the Müller glia, which displayed prominent cellular compartments containing apoptotic cells, several of which localized with the early phagosome/endosome marker Rab5. Consistent with increased engulfment, lysosomal staining was also increased in Müller glia in the absence of microglia. Increased engulfment load led to evidence of Müller glia reactivity including upregulation of gfap but did not trigger cell cycle re‐entry by differentiated Müller glia. Our work provides important insight into the phagocytic capacity of Müller glia and the ability for compensatory functions and downstream effects. Therefore, effects of microglial deficiency or depletion on other glial cell types should be well‐considered in experimental manipulations, in neurodegenerative disease, and in therapeutic approaches that target microglia. Our findings further justify future work to understand differential mechanisms and contexts of phagocytosis by glial cells in the central nervous system, and the significance of these mechanisms in health and disease.

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“…Figs. [4][5][6][7][8][9][10][11][12][13][14]. GO, KEGG (via pathfindR), and IPA analysis tools were used to assess DEG subsets exhibiting broadly correlated gene expression patterns (Fig.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic comparison of two selective retinal cell ablation paradigms in zebrafish reveals shared and cell-specific regenerative responses

Walker

Wang

Emmerich

et al. 2020

Preprint

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Zebrafish are an effective model organism for retinal regeneration studies. Regenerated retinal cells are derived from Müller glia (MG) stem cells. Mammalian MG can also produce new retinal neurons; however, this regenerative potential remains dormant in the absence of genetic and/or chemical stimulation. An understanding of how the regenerative potential of MG is regulated could aid efforts to promote regeneration therapeutically. Following widespread retinal cell death, developmental signaling coordinates regeneration. Less is known about how MG respond to the loss of specific cell types, i.e., paradigms similar to retinal degenerative diseases. To address this, transcriptomic responses to the selective loss of rod photoreceptors or retinal bipolar cells were compared over twelve timepoints spanning cell degeneration and regeneration. Shared and paradigm-specific expression changes were identified throughout regeneration. Overall, paradigm-specific changes predominated, suggesting cell-specific mechanisms for activating MG stem cells. One particularly interested finding new for retinal regeneration was early regulation of SOCS family genes. These are associated with stat3 activation and the JAK/STAT pathway which has been well documented in similar studies and was further supported in our analyses. These data support the concept that selective retinal cell loss can elicit cell-specific regenerative programs and provide novel insights into retinal regeneration.

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

Cited by 111 publications

References 48 publications

Deciphering the Retinal Epigenome during Development, Disease and Reprogramming: Advancements, Challenges and Perspectives

Deciphering the Retinal Epigenome during Development, Disease and Reprogramming: Advancements, Challenges and Perspectives

Compensatory engulfment and Müller glia reactivity in the absence of microglia

Transcriptomic comparison of two selective retinal cell ablation paradigms in zebrafish reveals shared and cell-specific regenerative responses

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