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 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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Shepherd, R. K., Shivdasani, M. N., Nayagam, D. A., Williams, C. E. & Blamey, P. J. Visual prostheses for the blind. Trends Biotechnol. 31, 562–571 (2013).
Pearson, R. A. et al. Restoration of vision after transplantation of photoreceptors. Nature 485, 99–103 (2012). The first demonstration of vision recovery following rod precursor transplants into a genetic model of blindness.
Boye, S. E., Boye, S. L., Lewin, A. S. & Hauswirth, W. W. A comprehensive review of retinal gene therapy. Mol. Ther. 21, 509–519 (2013).
Sherpa, T. et al. Ganglion cell regeneration following whole-retina destruction in zebrafish. Dev. Neurobiol. 68, 166–181 (2008).
Lindsey, A. E. & Powers, M. K. Visual behavior of adult goldfish with regenerating retina. Vis. Neurosci. 24, 247–255 (2007).
Mensinger, A. F. & Powers, M. K. Visual function in regenerating teleost retina following cytotoxic lesioning. Vis. Neurosci. 16, 241–251 (1999).
Reichenbach, A. & Bringmann, A. New functions of Müller cells. Glia 61, 651–678 (2013). An excellent review of recently discovered functions of Müller glia.
Bringmann, A. et al. Role of retinal glial cells in neurotransmitter uptake and metabolism. Neurochem. Int. 54, 143–160 (2009).
Powell, C., Grant, A. R., Cornblath, E. & Goldman, D. Analysis of DNA methylation reveals a partial reprogramming of the Müller glia genome during retina regeneration. Proc. Natl Acad. Sci. USA 110, 19814–19819 (2013). This paper identifies a changing DNA methylation landscape as Müller glia transition to stem cells.
Ramachandran, R., Fausett, B. V. & Goldman, D. Ascl1a regulates Müller glia dedifferentiation and retinal regeneration through a Lin-28-dependent, let-7 microRNA signalling pathway. Nature Cell Biol. 12, 1101–1107 (2010). This paper identifies pluripotency factors participating in Müller glial cell reprogramming and retina regeneration. It reveals a Lin28–let-7 miRNA signalling loop that is common to Müller glial cell reprogramming, embryonic stem cells and iPSCs.
Fausett, B. V. & Goldman, D. A role for α1 tubulin-expressing Müller glia in regeneration of the injured zebrafish retina. J. Neurosci. 26, 6303–6313 (2006). This is the first paper to report the use of transgenic zebrafish and BrdU lineage tracing to show that Müller glia are the source of retinal progenitors for retina regeneration in zebrafish and that these cells can regenerate all major retinal cell types.
Qin, Z., Barthel, L. K. & Raymond, P. A. Genetic evidence for shared mechanisms of epimorphic regeneration in zebrafish. Proc. Natl Acad. Sci. USA 106, 9310–9315 (2009).
Nagashima, M., Barthel, L. K. & Raymond, P. A. A self-renewing division of zebrafish Müller glial cells generates neuronal progenitors that require N-cadherin to regenerate retinal neurons. Development 140, 4510–4521 (2013). This study demonstrates interkinetic nuclear migration, asymmetrical division and the participation of N-cadherin in the generation of a Müller glial cell-derived progenitor.
Kassen, S. C. et al. Time course analysis of gene expression during light-induced photoreceptor cell death and regeneration in albino zebrafish. Dev. Neurobiol. 67, 1009–1031 (2007).
Turner, D. L. & Cepko, C. L. A common progenitor for neurons and glia persists in rat retina late in development. Nature 328, 131–136 (1987).
Jadhav, A. P., Roesch, K. & Cepko, C. L. Development and neurogenic potential of Müller glial cells in the vertebrate retina. Prog. Retin. Eye Res. 28, 249–262 (2009).
Jadhav, A. P., Cho, S. H. & Cepko, C. L. Notch activity permits retinal cells to progress through multiple progenitor states and acquire a stem cell property. Proc. Natl Acad. Sci. USA 103, 18998–19003 (2006).
Furukawa, T., Mukherjee, S., Bao, Z. Z., Morrow, E. M. & Cepko, C. L. rax, Hes1, and notch1 promote the formation of Müller glia by postnatal retinal progenitor cells. Neuron 26, 383–394 (2000).
Goureau, O., Rhee, K. D. & Yang, X. J. Ciliary neurotrophic factor promotes Müller glia differentiation from the postnatal retinal progenitor pool. Dev. Neurosci. 26, 359–370 (2004).
Bhattacharya, S., Das, A. V., Mallya, K. B. & Ahmad, I. Ciliary neurotrophic factor-mediated signaling regulates neuronal versus glial differentiation of retinal stem cells/progenitors by concentration-dependent recruitment of mitogen-activated protein kinase and Janus kinase-signal transducer and activator of transcription pathways in conjunction with Notch signaling. Stem Cells 26, 2611–2624 (2008).
Reichenbach, A. & Reichelt, W. Postnatal development of radial glial (Müller) cells of the rabbit retina. Neurosci. Lett. 71, 125–130 (1986).
Magalhaes, M. M. & Coimbra, A. The rabbit retina Müller cell. A fine structural and cytochemical study. J. Ultrastruct. Res. 39, 310–326 (1972).
Bringmann, A. et al. Cellular signaling and factors involved in Müller cell gliosis: neuroprotective and detrimental effects. Prog. Retin. Eye Res. 28, 423–451 (2009).
Tout, S., Chan-Ling, T., Hollander, H. & Stone, J. The role of Müller cells in the formation of the blood–retinal barrier. Neuroscience 55, 291–301 (1993).
Shen, W. et al. Conditional Müller cell ablation causes independent neuronal and vascular pathologies in a novel transgenic model. J. Neurosci. 32, 15715–15727 (2012).
Nagelhus, E. A. et al. Immunogold evidence suggests that coupling of K+ siphoning and water transport in rat retinal Müller cells is mediated by a coenrichment of Kir4.1 and AQP4 in specific membrane domains. Glia 26, 47–54 (1999).
Pow, D. V. & Crook, D. K. Direct immunocytochemical evidence for the transfer of glutamine from glial cells to neurons: use of specific antibodies directed against the D-stereoisomers of glutamate and glutamine. Neuroscience 70, 295–302 (1996).
Schutte, M. & Werner, P. Redistribution of glutathione in the ischemic rat retina. Neurosci. Lett. 246, 53–56 (1998).
Seki, M., Nawa, H., Fukuchi, T., Abe, H. & Takei, N. BDNF is upregulated by postnatal development and visual experience: quantitative and immunohistochemical analyses of BDNF in the rat retina. Invest. Ophthalmol. Vis. Sci. 44, 3211–3218 (2003).
Long, K. O., Fisher, S. K., Fariss, R. N. & Anderson, D. H. Disc shedding and autophagy in the cone-dominant ground squirrel retina. Exp. Eye Res. 43, 193–205 (1986).
Wang, J. S. & Kefalov, V. J. The cone-specific visual cycle. Prog. Retin. Eye Res. 30, 115–128 (2011).
Wang, X., Iannaccone, A. & Jablonski, M. M. Contribution of Müller cells toward the regulation of photoreceptor outer segment assembly. Neuron Glia Biol. 1, 1–6 (2005).
Franze, K. et al. Müller cells are living optical fibers in the vertebrate retina. Proc. Natl Acad. Sci. USA 104, 8287–8292 (2007).
Weissman, T., Noctor, S. C., Clinton, B. K., Honig, L. S. & Kriegstein, A. R. Neurogenic radial glial cells in reptile, rodent and human: from mitosis to migration. Cereb. Cortex 13, 550–559 (2003).
Blackshaw, S. et al. Genomic analysis of mouse retinal development. PLoS Biol. 2, E247 (2004).
Trimarchi, J. M., Stadler, M. B. & Cepko, C. L. Individual retinal progenitor cells display extensive heterogeneity of gene expression. PLoS ONE 3, e1588 (2008).
Roesch, K. et al. The transcriptome of retinal Müller glial cells. J. Comp. Neurol. 509, 225–238 (2008). An analysis of the mouse Müller glial cell transcriptome at the single cell level suggests some similarity with retinal progenitors and that there may be heterogeneity among Müller glia.
Del Debbio, C. B. et al. Notch and Wnt signaling mediated rod photoreceptor regeneration by Müller cells in adult mammalian retina. PLoS ONE 5, e12425 (2010).
Fischer, A. J. & Reh, T. A. Müller glia are a potential source of neural regeneration in the postnatal chicken retina. Nature Neurosci. 4, 247–252 (2001). An important paper that focused the field of retina regeneration on Müller glia as a source of retinal progenitors that could be used for repair.
Karl, M. O. et al. Stimulation of neural regeneration in the mouse retina. Proc. Natl Acad. Sci. USA 105, 19508–19513 (2008).
Ooto, S. et al. Potential for neural regeneration after neurotoxic injury in the adult mammalian retina. Proc. Natl Acad. Sci. USA 101, 13654–13659 (2004). This study identified Müller glia as a source of new neurons in the mammalian retina.
Osakada, F. et al. Wnt signaling promotes regeneration in the retina of adult mammals. J. Neurosci. 27, 4210–4219 (2007). This study indicates that WNT signalling may control the generation of Müller glial cell-derived progenitors in mammals.
Takeda, M. et al. α-Aminoadipate induces progenitor cell properties of Müller glia in adult mice. Invest. Ophthalmol. Vis. Sci. 49, 1142–1150 (2008).
Wan, J. et al. Preferential regeneration of photoreceptor from Müller glia after retinal degeneration in adult rat. Vision Res. 48, 223–234 (2008).
Gohdo, T., Ueda, H., Ohno, S., Iijima, H. & Tsukahara, S. Heat shock protein 70 expression increased in rabbit Müller cells in the ischemia-reperfusion model. Ophthalmic Res. 33, 298–302 (2001).
Paasche, G., Huster, D. & Reichenbach, A. The glutathione content of retinal Müller (glial) cells: the effects of aging and of application of free-radical scavengers. Ophthalmic Res. 30, 351–360 (1998).
Ghai, K., Zelinka, C. & Fischer, A. J. Notch signaling influences neuroprotective and proliferative properties of mature Müller glia. J. Neurosci. 30, 3101–3112 (2010).
Hayes, S., Nelson, B. R., Buckingham, B. & Reh, T. A. Notch signaling regulates regeneration in the avian retina. Dev. Biol. 312, 300–311 (2007).
Fischer, A. J. & Reh, T. A. Exogenous growth factors stimulate the regeneration of ganglion cells in the chicken retina. Dev. Biol. 251, 367–379 (2002).
Fischer, A. J., McGuire, C. R., Dierks, B. D. & Reh, T. A. Insulin and fibroblast growth factor 2 activate a neurogenic program in Müller glia of the chicken retina. J. Neurosci. 22, 9387–9398 (2002).
Ritchey, E. R., Zelinka, C. P., Tang, J., Liu, J. & Fischer, A. J. The combination of IGF1 and FGF2 and the induction of excessive ocular growth and extreme myopia. Exp. Eye Res. 99, 1–16 (2012).
Fischer, A. J., Scott, M. A. & Tuten, W. Mitogen-activated protein kinase-signaling stimulates Müller glia to proliferate in acutely damaged chicken retina. Glia 57, 166–181 (2009).
Das, A. V. et al. Neural stem cell properties of Müller glia in the mammalian retina: regulation by Notch and Wnt signaling. Dev. Biol. 299, 283–302 (2006).
Lawrence, J. M. et al. MIO-M1 cells and similar Müller glial cell lines derived from adult human retina exhibit neural stem cell characteristics. Stem Cells 25, 2033–2043 (2007).
Singhal, S. et al. Human Müller glia with stem cell characteristics differentiate into retinal ganglion cell (RGC) precursors in vitro and partially restore RGC function in vivo following transplantation. Stem Cells Transl. Med. 1, 188–199 (2012).
Jayaram, H. et al. Transplantation of photoreceptors derived from human Müller glia restore rod function in the P23H rat. Stem Cells Transl. Med. 3, 323–333 (2014).
Giannelli, S. G., Demontis, G. C., Pertile, G., Rama, P. & Broccoli, V. Adult human Müller glia cells are a highly efficient source of rod photoreceptors. Stem Cells 29, 344–356 (2011).
Wan, J., Zheng, H., Xiao, H. L., She, Z. J. & Zhou, G. M. Sonic hedgehog promotes stem-cell potential of Müller glia in the mammalian retina. Biochem. Biophys. Res. Commun. 363, 347–354 (2007).
Pollak, J. et al. ASCL1 reprograms mouse Müller glia into neurogenic retinal progenitors. Development 140, 2619–2631 (2013). This report shows ASCL1 overexpresssion can drive Müller glial cell reprogramming in postnatal mice. Interestingly, this protein also drives Müller glial cell reprogramming in zebrafish (see references 10, 63 and 64).
Close, J. L., Liu, J., Gumuscu, B. & Reh, T. A. Epidermal growth factor receptor expression regulates proliferation in the postnatal rat retina. Glia 54, 94–104 (2006).
Close, J. L., Gumuscu, B. & Reh, T. A. Retinal neurons regulate proliferation of postnatal progenitors and Müller glia in the rat retina via TGF β signaling. Development 132, 3015–3026 (2005).
Ueki, Y. & Reh, T. A. EGF stimulates Müller glial proliferation via a BMP-dependent mechanism. Glia 61, 778–789 (2013).
Ramachandran, R., Zhao, X. F. & Goldman, D. Ascl1a/Dkk/β-catenin signaling pathway is necessary and glycogen synthase kinase-3β inhibition is sufficient for zebrafish retina regeneration. Proc. Natl Acad. Sci. USA 108, 15858–15863 (2011). This paper shows that Wnt signalling is necessary for retina regeneration in the injured zebrafish retina and that Gsk3β inhibition suffices to drive Müller glial cell reprogramming in the uninjured retina.
Fausett, B. V., Gumerson, J. D. & Goldman, D. The proneural basic helix-loop-helix gene ascl1a is required for retina regeneration. J. Neurosci. 28, 1109–1117 (2008).
Johns, P. R. Growth of the adult goldfish eye. III. Source of the new retinal cells. J. Comp. Neurol. 176, 343–357 (1977).
Johns, P. R. & Fernald, R. D. Genesis of rods in teleost fish retina. Nature 293, 141–142 (1981).
Bernardos, R. L., Barthel, L. K., Meyers, J. R. & Raymond, P. A. Late-stage neuronal progenitors in the retina are radial Müller glia that function as retinal stem cells. J. Neurosci. 27, 7028–7040 (2007).
Thummel, R., Kassen, S. C., Montgomery, J. E., Enright, J. M. & Hyde, D. R. Inhibition of Müller glial cell division blocks regeneration of the light-damaged zebrafish retina. Dev. Neurobiol. 68, 392–408 (2008).
Fimbel, S. M., Montgomery, J. E., Burket, C. T. & Hyde, D. R. Regeneration of inner retinal neurons after intravitreal injection of ouabain in zebrafish. J. Neurosci. 27, 1712–1724 (2007).
Hitchcock, P. F. et al. Local regeneration in the retina of the goldfish. J. Neurobiol. 23, 187–203 (1992).
Braisted, J. E. & Raymond, P. A. Regeneration of dopaminergic neurons in goldfish retina. Development 114, 913–919 (1992).
Raymond, P. A., Reifler, M. J. & Rivlin, P. K. Regeneration of goldfish retina: rod precursors are a likely source of regenerated cells. J. Neurobiol. 19, 431–463 (1988).
Braisted, J. E., Essman, T. F. & Raymond, P. A. Selective regeneration of photoreceptors in goldfish retina. Development 120, 2409–2419 (1994).
Hitchcock, P. F. & Vanderyt, J. T. Regeneration of the dopamine-cell mosaic in the retina of the goldfish. Vis. Neurosci. 11, 209–217 (1994).
Braisted, J. E. & Raymond, P. A. Continued search for the cellular signals that regulate regeneration of dopaminergic neurons in goldfish retina. Brain Res. Dev. Brain Res. 76, 221–232 (1993).
Wu, D. M. et al. Cones regenerate from retinal stem cells sequestered in the inner nuclear layer of adult goldfish retina. Invest. Ophthalmol. Vis. Sci. 42, 2115–2124 (2001).
Otteson, D. C., D'Costa, A. R. & Hitchcock, P. F. Putative stem cells and the lineage of rod photoreceptors in the mature retina of the goldfish. Dev. Biol. 232, 62–76 (2001).
Yurco, P. & Cameron, D. A. Responses of Müller glia to retinal injury in adult zebrafish. Vision Res. 45, 991–1002 (2005).
Senut, M. C., Gulati-Leekha, A. & Goldman, D. An element in the α1-tubulin promoter is necessary for retinal expression during optic nerve regeneration but not after eye injury in the adult zebrafish. J. Neurosci. 24, 7663–7673 (2004).
Ramachandran, R., Reifler, A., Parent, J. M. & Goldman, D. Conditional gene expression and lineage tracing of tuba1a expressing cells during zebrafish development and retina regeneration. J. Comp. Neurol. 518, 4196–4212 (2010).
Vihtelic, T. S. & Hyde, D. R. Light-induced rod and cone cell death and regeneration in the adult albino zebrafish (Danio rerio) retina. J. Neurobiol. 44, 289–307 (2000).
Montgomery, J. E., Parsons, M. J. & Hyde, D. R. A novel model of retinal ablation demonstrates that the extent of rod cell death regulates the origin of the regenerated zebrafish rod photoreceptors. J. Comp. Neurol. 518, 800–814 (2010).
Wan, J., Ramachandran, R. & Goldman, D. HB-EGF is necessary and sufficient for Müller glia dedifferentiation and retina regeneration. Dev. Cell 22, 334–347 (2012). In addition to showing that HBEGF stimulates Müller glial cell reprogramming, this paper also demonstrates a role for Notch signalling in restricting the zone of injury-responsive Müller glia in the injured retina.
Nelson, C. M. et al. Tumor necrosis factor-α is produced by dying retinal neurons and is required for Müller glia proliferation during zebrafish retinal regeneration. J. Neurosci. 33, 6524–6539 (2013). This paper suggests Tnfα may initiate the injury response in Müller glia, as it is produced by injured cells and is necessary for stimulating the proliferation of Müller glia.
Kassen, S. C. et al. CNTF induces photoreceptor neuroprotection and Müller glial cell proliferation through two different signaling pathways in the adult zebrafish retina. Exp. Eye Res. 88, 1051–1064 (2009).
Faillace, M. P., Julian, D. & Korenbrot, J. I. Mitotic activation of proliferative cells in the inner nuclear layer of the mature fish retina: regulatory signals and molecular markers. J. Comp. Neurol. 451, 127–141 (2002).
Battista, A. G., Ricatti, M. J., Pafundo, D. E., Gautier, M. A. & Faillace, M. P. Extracellular ADP regulates lesion-induced in vivo cell proliferation and death in the zebrafish retina. J. Neurochem. 111, 600–613 (2009).
Nelson, C. M. et al. Stat3 defines three populations of Müller glia and is required for initiating maximal Müller glia proliferation in the regenerating zebrafish retina. J. Comp. Neurol. 520, 4294–4311 (2012). This paper identifies a range of Müller glial cell populations that increase Stat3 expression following retinal injury and suggests multiple roles for Stat3 in the injured retina.
Craig, S. E., Calinescu, A. A. & Hitchcock, P. F. Identification of the molecular signatures integral to regenerating photoreceptors in the retina of the zebra fish. J. Ocul. Biol. Dis. Infor. 1, 73–84 (2008).
Zelinka, C., Scott, M. & Fischer, A. Reactive microglia and the formation of Müller glia-derived retinal progenitors. ARVO Meet. Abstr. 54, 5583 (2013).
Bailey, T. J., Fossum, S. L., Fimbel, S. M., Montgomery, J. E. & Hyde, D. R. The inhibitor of phagocytosis, O-phospho-l-serine, suppresses Müller glia proliferation and cone cell regeneration in the light-damaged zebrafish retina. Exp. Eye Res. 9, 601–612 (2010).
Meyers, J. R. et al. β-catenin/Wnt signaling controls progenitor fate in the developing and regenerating zebrafish retina. Neural Dev. 7, 30 (2012).
Valenta, T., Hausmann, G. & Basler, K. The many faces and functions of β-catenin. EMBO J. 31, 2714–2736 (2012).
Lenkowski, J. R. et al. Retinal regeneration in adult zebrafish requires regulation of TGFβ signaling. Glia 61, 1687–1697 (2013).
Cameron, D. A., Gentile, K. L., Middleton, F. A. & Yurco, P. Gene expression profiles of intact and regenerating zebrafish retina. Mol. Vis. 11, 775–791 (2005).
Ramachandran, R., Zhao, X. F. & Goldman, D. Insm1a-mediated gene repression is essential for the formation and differentiation of Müller glia-derived progenitors in the injured retina. Nature Cell Biol. 14, 1013–1023 (2012). A remarkable demonstration of how a single transcription factor can stimulate the formation and differentiation of Muller glial cell-derived progenitors depending on the cellular environment it acts in.
Powell, C., Elsaeidi, F. & Goldman, D. Injury-dependent Müller glia and ganglion cell reprogramming during tissue regeneration requires Apobec2a and Apobec2b. J. Neurosci. 32, 1096–1109 (2012).
Thummel, R. et al. Pax6a and Pax6b are required at different points in neuronal progenitor cell proliferation during zebrafish photoreceptor regeneration. Exp. Eye Res. 90, 572–582 (2010). An important paper demonstrating the role of Pax6 proteins in the first divisions of Müller glial cell-derived progenitors.
Craig, S. E. et al. The zebrafish galectin Drgal1-l2 is expressed by proliferating Müller glia and photoreceptor progenitors and regulates the regeneration of rod photoreceptors. Invest. Ophthalmol. Vis. Sci. 51, 3244–3252 (2010).
Raymond, P. A., Barthel, L. K., Bernardos, R. L. & Perkowski, J. J. Molecular characterization of retinal stem cells and their niches in adult zebrafish. BMC Dev. Biol. 6, 36 (2006).
Calinescu, A. A., Vihtelic, T. S., Hyde, D. R. & Hitchcock, P. F. Cellular expression of midkine-a and midkine-b during retinal development and photoreceptor regeneration in zebrafish. J. Comp. Neurol. 514, 1–10 (2009).
Shyh-Chang, N. & Daley, G. Q. Lin28: primal regulator of growth and metabolism in stem cells. Cell Stem Cell 12, 395–406 (2013).
Melton, C., Judson, R. L. & Blelloch, R. Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature 463, 621–626 (2010).
Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).
Shyh-Chang, N. et al. Lin28 enhances tissue repair by reprogramming cellular metabolism. Cell 155, 778–792 (2013).
Rybak, A. et al. A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment. Nature Cell Biol. 10, 987–993 (2008).
Peng, S. et al. Genome-wide studies reveal that Lin28 enhances the translation of genes important for growth and survival of human embryonic stem cells. Stem Cells 29, 496–504 (2011).
Mikkelsen, T. S. et al. Dissecting direct reprogramming through integrative genomic analysis. Nature 454, 49–55 (2008).
Polo, J. M. et al. A molecular roadmap of reprogramming somatic cells into iPS cells. Cell 151, 1617–1632 (2012).
Karlic, R., Chung, H. R., Lasserre, J., Vlahovicek, K. & Vingron, M. Histone modification levels are predictive for gene expression. Proc. Natl Acad. Sci. USA 107, 2926–2931 (2010).
Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).
Morris, A. C., Scholz, T. L., Brockerhoff, S. E. & Fadool, J. M. Genetic dissection reveals two separate pathways for rod and cone regeneration in the teleost retina. Dev. Neurobiol. 68, 605–619 (2008).
Fraser, B., DuVal, M. G., Wang, H. & Allison, W. T. Regeneration of cone photoreceptors when cell ablation is primarily restricted to a particular cone subtype. PLoS ONE 8, e55410 (2013).
Ariga, J., Walker, S. L. & Mumm, J. S. Multicolor time-lapse imaging of transgenic zebrafish: visualizing retinal stem cells activated by targeted neuronal cell ablation. J. Vis. Exp. 43, e2093 (2010).
Qin, Z. et al. FGF signaling regulates rod photoreceptor cell maintenance and regeneration in zebrafish. Exp. Eye Res. 93, 726–734 (2011).
Kyritsis, N. et al. Acute inflammation initiates the regenerative response in the adult zebrafish brain. Science 338, 1353–1356 (2012).
Godwin, J. W., Pinto, A. R. & Rosenthal, N. A. Macrophages are required for adult salamander limb regeneration. Proc. Natl Acad. Sci. USA 110, 9415–9420 (2013).
Zelinka, C. P., Scott, M. A., Volkov, L. & Fischer, A. J. The reactivity, distribution and abundance of non-astrocytic innerretinal glial (NIRG) cells are regulated by microglia, acute damage, and IGF1. PLoS ONE 7, e44477 (2012).
Fang, Y. et al. Ephrin-A3 suppresses Wnt signaling to control retinal stem cell potency. Stem Cells 31, 349–359 (2013).
Jiao, J. W., Feldheim, D. A. & Chen, D. F. Ephrins as negative regulators of adult neurogenesis in diverse regions of the central nervous system. Proc. Natl Acad. Sci. USA 105, 8778–8783 (2008).
Balenci, L., Wonders, C., Coles, B. L., Clarke, L. & van der Kooy, D. Bone morphogenetic proteins and secreted frizzled related protein 2 maintain the quiescence of adult mammalian retinal stem cells. Stem Cells 31, 2218–2230 (2013).
Fischer, A. J., Scott, M. A., Ritchey, E. R. & Sherwood, P. Mitogen-activated protein kinase-signaling regulates the ability of Muller glia to proliferate and protect retinal neurons against excitotoxicity. Glia 57, 1538–1552 (2009).
Hochmann, S. et al. Fgf signaling is required for photoreceptor maintenance in the adult zebrafish retina. PLoS ONE 7, e30365 (2012).
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.
The author declares no competing financial interests.
- 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.
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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