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Müller glial cell reprogramming and retina regeneration

Key Points

  • The Müller glia of fish, birds and mammals share structure and function.

  • A key difference between Müller glia in fish and those in mammals is their ability to participate in retinal repair. Unlike those present in birds and mammals, fish Müller glia respond to retinal injury by undergoing a reprogramming event that enables them to acquire the properties of a retinal stem cell and generate multipotent progenitors for repair.

  • Various growth factors, cytokines and Wnts that are secreted from injured cells and Müller glia seem to drive Müller glial cell reprogramming in fish by activating signalling cascades that include mitogen-activated protein kinase (Mapk)–extracellular signal-regulated kinase (Erk), glycogen synthase kinase 3β (Gsk3β)–β-catenin and Janus kinase (Jak)–signal transducer and activator of transcription (Stat) signalling.

  • Growth factors and cytokines can stimulate Müller glial cell proliferation in damaged retinas of birds and mice, but these proliferating cells exhibit a very limited ability to regenerate new neurons and generally do not survive.

  • In fish, factors such as tumour necrosis factor-α (Tnfα), heparin-binding epidermal growth factor-like growth factor (Hbegf), achaete-scute homologue 1 (Ascl1a), Stat3 and Lin28 seem to regulate the earliest stages of Müller glial cell reprogramming, whereas paired box 6a (Pax6a) and Pax6b drive progenitor expansion and insulinoma-associated 1a (Insm1a) drives progenitors out of the cell cycle.

  • In zebrafish, in addition to the activation of gene expression programmes that drive Müller glial cell reprogramming, there is suppression of gene expression programmes that inhibit Müller glial cell reprogramming, such as those controlled by let-7 microRNAs, dickkopf, TGFβ-induced factor 1 (Tgif1) and sine oculis homeobox homologue 3b (Six3b).

  • Notch signalling stimulates the formation of Müller glial cell-derived progenitors in birds but inhibits the zone of injury-responsive Müller glia in fish.

  • Forced ASCL1 overexpression along with epidermal growth factor treatment can stimulate Müller glia in postnatal mouse retinal explants to reprogramme and generate bipolar neurons.

  • Müller glial cell reprogramming and retina regeneration are associated with changes in DNA methylation in fish; however, many key reprogramming genes exhibit a low basal level of methylation in the uninjured retinas of both fish and mice, suggesting that they may be poised for expression.

  • Studies that are unravelling the mechanisms underlying Müller glial cell reprogramming and retina regeneration in fish along with studies of Müller glia in other species, such as birds and mammals, may reveal novel strategies for stimulating retina regeneration in humans.

Abstract

Müller glia are the major glial component of the retina. They are one of the last retinal cell types to be born during development, and they function to maintain retinal homeostasis and integrity. In mammals, Müller glia respond to retinal injury in various ways that can be either protective or detrimental to retinal function. Although these cells can be coaxed to proliferate and generate neurons under special circumstances, these responses are meagre and insufficient for repairing a damaged retina. By contrast, in teleost fish (such as zebrafish), the response of Müller glia to retinal injury involves a reprogramming event that imparts retinal stem cell characteristics and enables them to produce a proliferating population of progenitors that can regenerate all major retinal cell types and restore vision. Recent studies have revealed several important mechanisms underlying Müller glial cell reprogramming and retina regeneration in fish that may lead to new strategies for stimulating retina regeneration in mammals.

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Figure 1: Retinal anatomy.
Figure 2: Generation of multipotent Müller glial cell-derived progenitors for retinal repair.
Figure 3: Injury paradigms and the communication of injury to Müller glia.
Figure 4: Signalling cascades that contribute to Müller glial cell reprogramming and progenitor proliferation in zebrafish.
Figure 5: Regeneration-associated transcriptional cascades in zebrafish.

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Acknowledgements

Research in the Goldman laboratory is supported by NEI grants RO1 EY 018132 and 1R21 EY022707 from the US National Institute of Health, an Innovative Ophthalmic Research Award from Research to Prevent Blindness and a gift from the Marjorie and Maxwell Jospey Foundation. The author thanks Goldman laboratory members C. Powell, J. Wan and X.-F. Zhao for helpful comments and suggestions on this Review.

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Glossary

Multipotent progenitors

Cells that have the potential to differentiate into more than a single cell type but are more restricted in their fate than embryonic stem cells.

Limiting membranes

The boundary between the retina and the vitreous is referred to as the inner limiting membrane and is composed of Müller glial cell endfeet and astrocytes. The outer limiting membrane forms a barrier between the neural retina and the subretinal space. The outer limiting membrane is formed by adherens junctions between Müller glia and photoreceptor inner segments.

Outer segments

Parts of photoreceptors that are adjacent to the retinal pigment epithelial cell layer. These segments contain membrane discs filled with opsin.

Retinal chromophore

A molecule that attaches to opsins to enable light absorption by photoreceptors.

Radial glia

Cells that span the radial axis of the developing cortex and function as precursors or guides for newly born postmitotic neurons migrating into the mantle zone.

Neuroepithelial cells

Neural stem cells that can self-renew and give rise to all neural cell types.

Transcriptome

The complete set of RNA molecules produced by a cell or a population of cells at a given time point.

Induced pluripotent stem cells

(iPSCs). A type of pluripotent stem cells that are generated from fully differentiated cells.

Reduced representation bisulphite sequencing

A high-throughput technique for analysing DNA methylation at the nucleotide level on a genome-wide scale.

Transient amplifying progenitors

Cells that arise from adult stem cells and divide a finite number of times until they become differentiated. They are committed progenitor cells.

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Goldman, D. Müller glial cell reprogramming and retina regeneration. Nat Rev Neurosci 15, 431–442 (2014). https://doi.org/10.1038/nrn3723

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