Müller glial cell reprogramming and retina regeneration

• Published in: Nature reviews. Neuroscience Vol. 15; no. 7; pp. 431 - 442
• Main Author: Goldman, Daniel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2014; Nature Publishing Group
• Subjects: 38; 42/41; 631/378/1687; 631/378/2596; 631/378/2613/1786; 631/378/87; 64/116; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedicine; Ependymoglial Cells - pathology; Ependymoglial Cells - physiology; Homeostasis; Humans; Kinases; Nerve Net - cytology; Nerve Net - pathology; Nerve Net - physiology; Nerve Regeneration - physiology; Neurobiology; Neuroglia; Neuroglia - pathology; Neuroglia - physiology; Neurosciences; Photoreceptors; Physiological aspects; Regeneration (Biology); Retina; Retina - cytology; Retina - pathology; Retina - physiology; review-article; Signal Transduction - physiology; Stem cells; Zebrafish
• ISSN: 1471-003X; 1471-0048; 1469-3178
• DOI: 10.1038/nrn3723

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. Müller glia in the fish retina respond to injury by reprogramming to a stem-cell-like state that enables them to regenerate all of the major retinal cell types. Goldman reviews our current understanding of the mechanisms that regulate this regenerative response and considers how this knowledge might be applied to improve repair in the mammalian retina. 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.