Wnt Regulates Proliferation and Neurogenic Potential of Müller Glial Cells via a Lin28/let-7 miRNA-Dependent Pathway in Adult Mammalian Retinas

Yao, Kai; Qiu, Suo; Tian, Lin; Snider, William D.; Flannery, John G.; Schaffer, David V.; Chen, Bin

doi:10.1016/j.celrep.2016.08.078

Cited by 128 publications

(177 citation statements)

References 61 publications

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“…There is evidence for cross-talk between many of these pathways with NF-ĸB signaling in different cellular contexts (Ahmad et al 2015;Ma and Hottiger 2016;Mohan et al 1998;Nelson et al 2013). For example, there is evidence of bidirectional communication between Wnt and NF-ĸB signaling, and we have previously shown that Wnt-signaling promotes formation of proliferating MGPCs in the chick retina (Gallina et al, 2015), which is consistent with findings in mouse and fish retinas (Meyers et al, 2012;Meyers et al, 2012;Osakada et al, 2007;Yao et al, 2016;Yao et al, 2018). It has been shown that over-expression of β-catenin, a transcriptional effector of Wnt, suppresses NF-ĸB activity and expression of NF-ĸB target genes (reviewed by (Ma and Hottiger, 2016).…”

Section: Discussionsupporting

confidence: 85%

NF-κB signaling regulates the formation of proliferating Müller glia-derived progenitor cells in the avian retina

Palazzo

Deistler

Hoang

et al. 2019

Preprint

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AbstractNeuronal regeneration in the retina is a robust, effective process in some cold-blooded vertebrates, but this process is ineffective in warm-blooded vertebrates. Understanding the mechanisms and cell-signaling pathways that restrict the reprogramming of Müller glia into proliferating neurogenic progenitors is key to harnessing the regenerative potential of the retina. Inflammation and reactive microglia are known to influence the formation of Müller glia-derived progenitor cells (MGPCs), but the mechanisms underlying this response are unknown. Using the chick retina in vivo as a model system, we investigate the role of the Nuclear Factor kappa B (NF-κB) signaling, a critical regulator of inflammation. We find that components of the NF-κB pathway are expressed by Müller glia and are dynamically regulated after neuronal damage or treatment with growth factors. Inhibition of NF-κB enhances, whereas activation suppresses the formation of proliferating MGPCs. Additionally, activation of NF-κB promotes glial differentiation from MGPCs in damaged retinas. With microglia ablated, the effects of NF-κB-agonists/antagonists on MGPC formation are reversed, suggesting that the context and timing of signals provided by reactive microglia influence how NF-κB-signaling impacts the reprogramming of Müller glia. We propose that NF-κB-signaling is an important signaling “hub” that suppresses the reprogramming of Müller glia into proliferating MGPCs and this “hub” coordinates signals provided by reactive microglia.

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Section: Discussionsupporting

confidence: 85%

NF-κB signaling regulates the formation of proliferating Müller glia-derived progenitor cells in the avian retina

Palazzo

Deistler

Hoang

et al. 2019

Preprint

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“…However, the study presented here demonstrates that PNU-282987 was able to elicit a significant neurogenic response through Müller glia without triggering apoptosis, as indicated by the lack of caspase 3 activity. Interestingly, recent work in adult mice has shown that modulation of Wnt signaling can also induce cell cycle rentry in Müller glia (Yao et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

Evidence of BrdU-positive retinal neurons after application of an Alpha7 nicotinic acetylcholine receptor agonist

et al. 2017

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Irreversible vision loss due to disease or age is responsible for a reduced quality of life. The experiments in this study test the hypothesis that the α7 nicotinic acetylcholine receptor agonist, PNU-282987, leads to the generation of retinal neurons in an adult mammalian retina in the absence of retinal injury or exogenous growth factors. Using antibodies against BrdU, retinal ganglion cells, progenitor cells and Müller glia, the results of this study demonstrate that multiple types of retinal cells and neurons are generated after eye drop application of PNU-282987 in adult Long Evans rats in a dose-dependent manner. The results of this study provide evidence that progenitor cells, derived from Müller glia after treatment with PNU-282987, differentiate and migrate to the photoreceptor and retinal ganglion cell layers. If retinas were treated with the alpha7 nAChR antagonist, methyllycaconitine, before agonist treatment, BrdU positive cells were significantly reduced. As adult mammalian neurons do not typically regenerate or proliferate, these results have implications for reversing vision loss due to neurodegenerative disease or the aging process to improve the quality of life for millions of patients.

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“…In contrast, mammalian MG undergo reactive gliosis upon retinal injury and disease, but do not naturally regenerate lost cells (Fischer & Reh, 2003;Inman & Horner, 2007;Karl & Reh, 2010;Reichenbach & Bringmann, 2013). During the last decade, various evidence has indicated that a limited amount of MG-derived neuronal regeneration can be experimentally stimulated in rodents (Del Debbio et al, 2010;Giannelli, Demontis, Pertile, Rama, & Broccoli, 2011;Harada et al, 2011;Insua et al, 2008;Jayaram et al, 2014;Joly, Pernet, Samardzija, & Grimm, 2011;Karl et al, 2008;Lawrence et al, 2007;Ooto et al, 2004;Osakada et al, 2007;Pollak et al, 2013;Reyes-Aguirre et al, 2013;Takeda et al, 2008;Ueki et al, 2015;Wan et al, 2008;Wan, Zheng, Xiao, She, & Zhou, 2007;Wang et al, 2012;Yao et al, 2016;Zhao et al, 2014), and that the extent might depend on animal age (Close, Liu, Gumuscu, & Reh, 2006;L€ offler, et al, 2015;Ueki et al, 2012) and the mouse strain (Suga, Sadamoto, Fujii, Mandai, & Takahashi, 2014).…”

mentioning

confidence: 99%

Prospective purification and characterization of Müller glia in the mouse retina regeneration assay

Patrick

Karl

2017

Glia

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Reactive gliosis is an umbrella term for various glia functions in neurodegenerative diseases and upon injury. Specifically, Müller glia (MG) in some species readily regenerate retinal neurons to restore vision loss after insult, whereas mammalian MG respond by reactive gliosis-a heterogeneous response which frequently includes cell hypertrophy and proliferation. Limited regeneration has been stimulated in mammals, with a higher propensity in young MG, and in vitro compared to in vivo, but the underlying processes are unknown. To facilitate studies on the mechanisms regulating and limiting glia functions, we developed a strategy to purify glia and their progeny by fluorescence-activated cell sorting. Dual-transgenic nuclear reporter mice, which label neurons and glia with red and green fluorescent proteins, respectively, have enabled MG enrichment up to 93% purity. We applied this approach to MG in a mouse retina regeneration ex vivo assay. Combined cell size and cell cycle analysis indicates that most MG hypertrophy and a subpopulation proliferates which, over time, become even larger in cell size than the ones that do not proliferate. MG undergo timed differential genomic changes in genes controlling stemness and neurogenic competence; and glial markers are downregulated. Genes that are potentially required for, or associated with, regeneration and reactive gliosis are differentially regulated by retina explant culture time, epidermal growth factor stimulation, and animal age. Thus, MG enrichment facilitates cellular and molecular studies which, in combination with the mouse retina regeneration assay, provide an experimental approach for deciphering mechanisms that possibly regulate reactive gliosis and limit regeneration in mammals.

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Wnt Regulates Proliferation and Neurogenic Potential of Müller Glial Cells via a Lin28/let-7 miRNA-Dependent Pathway in Adult Mammalian Retinas

Cited by 128 publications

References 61 publications

NF-κB signaling regulates the formation of proliferating Müller glia-derived progenitor cells in the avian retina

NF-κB signaling regulates the formation of proliferating Müller glia-derived progenitor cells in the avian retina

Evidence of BrdU-positive retinal neurons after application of an Alpha7 nicotinic acetylcholine receptor agonist

Prospective purification and characterization of Müller glia in the mouse retina regeneration assay

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