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

Palazzo, Isabella; Deistler, Kyle; Hoang, Thanh; Blackshaw, Seth; Fischer, Andy J.

doi:10.1242/dev.183418

Cited by 55 publications

(78 citation statements)

References 101 publications

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“…These findings indicate that shortly after acute retinal injury, MG activate a program involving NFkB signaling, TGFb signaling, and Id transcription factors that suppress neurogenic potential, and likely act to restore and maintain glial phenotype. This is consistent with our findings in the chick retina that activation of NFkB signaling suppresses the formation of MGPCs and promotes differentiation of progeny into glial cells 15 .…”

Section: Discussionsupporting

confidence: 93%

“…In the zebrafish, inflammatory signals are necessary for MG reprogramming and ablation of microglia in the retina prior to injury impairs the process of neuronal regeneration 33,67 . In the chick retina, the ablation of microglia in the retina prevents the formation of proliferating MGPCs 68 , but this can be rescued by delivery of a pro-inflammatory cytokine (TNFSF15) or by pharmacological activation of NFkB-signaling 15 . However, in mammalian retinas, microglia interfere with MG-mediated neuronal regeneration; ablation of microglia promotes Ascl1-mediated neurogenesis and treatment with TNF decreases Ascl1-mediated MG reprogramming 23 .…”

Section: Discussionmentioning

confidence: 99%

“…Lastly, we assayed for changed in cell death considering previous studies indicating that inhibition of NFkB is neuroprotective against NMDA-induced damage in mammalian 16,17 and avian 15 retinas. We found a significant decrease in the number of TUNEL positive cells in retinas of Rlbp1-CreERT:Ikkb fl/fl mice compared to Rlbp1-CreERT control mice at 48hr after NMDA treatment (Fig.…”

Section: Conditional Knockout Of Nfkb Signaling In Mg Impairs Immune Cell Responses In Damaged Retinasmentioning

confidence: 99%

“…Thus, we hypothesize that NFkB signaling may be part of the regulatory networks that drive reactive MG to restore quiescence and suppress gene modules that promote the de-differentiation and the formation of neurogenic progenitors. We have recently reported that NFkB signaling in the chick retina suppresses the formation of MGPCs and this process depends on signals from reactive microglia 15 . NFkB signaling is activated in the retina following different types of neuronal damage [16][17][18] or chronic degeneration 19,20 .…”

Section: Introductionmentioning

confidence: 99%

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NFkB-signaling promotes glial reactivity and suppresses Müller glia-mediated neuron regeneration in the mammalian retina

Palazzo

Todd²,

Hoang³

et al. 2021

Preprint

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Müller glia (MG) in mammalian retinas are incapable of regenerating neurons after damage, whereas the MG in lower vertebrates regenerate functional neurons. Identification networks that regulate MG-mediated regeneration is key to harnessing the regenerative potential of MG. Here we study how NFkB-signaling influences glial responses to damage and reprogramming of MG into neurons in the rodent retina. We find activation of NFkB and dynamic expression of NFkB-associated genes in MG after damage, however NFkB activity is inhibited by microglia ablation. Knockout of NFkB in MG suppressed the accumulation of immune cells after damage. Inhibition of NFkB following NMDA-damage significantly enhanced the reprogramming of Ascl1-overexpressing MG into neuron-like cells. scRNA-seq of retinal glia following inhibition of NFkB reveals coordination with signaling via TGFb2 and suppression of NFI and Id transcription factors. Inhibition of Smad3 or Id transcription factors increased numbers of neuron-like cells produced by Ascl1-overexpressing MG. We conclude that NFkB is a key signaling hub that is activated in MG after damage, mediates the accumulation of immune cells, and suppresses the neurogenic potential of MG.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Conditional Knockout Of Nfkb Signaling In Mg Impairs Immune Cell Responses In Damaged Retinasmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

NFkB-signaling promotes glial reactivity and suppresses Müller glia-mediated neuron regeneration in the mammalian retina

Palazzo

Todd²,

Hoang³

et al. 2021

Preprint

Self Cite

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“…Most of the recent developments were reported in either cold-blooded or warm-blooded vertebrates, some of of 12 which investigated molecular pathways that may improve the current understanding of the reprogramming of Müller glia in mammals. For example, a recent study by Palazzo et al (2019) investigated the role of the Nuclear Factor Kappa B (NF-kB) pathway in Müller glia reprogramming in chick embryos, which showed that a component of the NF-kB pathway expressed by Müller cells, inhibits the reprogramming of Müller glia into retinal neurons [79], providing targets that can potentially be responsible for the lack of regeneration of mammalian Müller cells into retinal neurones.…”

Section: Current Understanding Of the Regeneration Potential Of Müller Glia In Mammalsmentioning

confidence: 99%

Insights on the Regeneration Potential of Müller Glia in the Mammalian Retina

Salman

McClements

MacLaren

2021

Cells

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Müller glia, the major glial cell types in the retina, maintain retinal homeostasis and provide structural support to retinal photoreceptors. They also possess regenerative potential that might be used for retinal repair in response to injury or disease. In teleost fish (such as zebrafish), the Müller glia response to injury involves reprogramming events that result in a population of proliferative neural progenitors that can regenerate the injured retina. Recent studies have revealed several important mechanisms for the regenerative capacity of Müller glia in fish, which may shed more light on the mechanisms of Müller glia reprogramming and regeneration in mammals. Mammalian Müller glia can adopt stem cell characteristics, and in response to special conditions, be persuaded to proliferate and regenerate, although their native regeneration potential is limited. In this review, we consider the work to date revealing the regenerative potential of the mammalian Müller glia and discuss whether they are a potential source for cell regeneration therapy in humans.

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Nuclear Factor I in neurons, glia and during the formation of Müller glia‐derived progenitor cells in avian, porcine and primate retinas

El‐Hodiri

Campbell

Kelly

et al. 2021

J of Comparative Neurology

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The regenerative potential of Müller glia (MG) is extraordinary in fish, poor in chick and terrible in mammals. In the chick model, MG readily reprogram into proliferating Müller glia-derived progenitor cells (MGPCs), but neuronal differentiation is very limited. The factors that suppress the neurogenic potential of MGPCs in the chick are slowly being revealed. Isoforms of Nuclear Factor I (NFI) are cell-intrinsic factors that limit neurogenic potential; these factors are required for the formation of MG in the developing mouse retina and deletion of these factors reprograms MG into neuronlike cells in mature mouse retina. Accordingly, we sought to characterize the patterns of expression of NFIs in the developing, mature and damaged chick retina. In addition, we characterized patterns of expression of NFIs in the retinas of large mammals, pigs and monkeys. Using a combination of single-cell RNA-sequencing (scRNA-seq) and immunolabeling, we probed for patterns of expression. In embryonic chick, levels of NFIs are very low in early E5 (embryonic day 5) retinal progenitor cells (RPCs), upregulated in E8 RPCs, further upregulated in differentiating MG at E12 and E15. NFIs are maintained in mature resting MG, microglia and neurons. Levels of NFIs are reduced in activated MG in retinas treated with NMDA and/or insulin+FGF2, and further downregulated in proliferating MGPCs. However, levels of NFIs in MGPCs were significantly higher than those seen in RPCs. Immunolabeling for NFIA and NFIB closely matched patterns of expression revealed in different types of retinal neurons and glia, consistent with findings from scRNA-seq. In addition, we find expression of NFIA and NFIB through progenitors in the circumferential marginal zone at the far periphery of the retina. We find similar patterns of expression for NFIs in scRNA-seq databases for pig and monkey retinas. Patterns of expression of NFIA and NFIB were validated with immunofluorescence in pig and monkey retinas wherein these factors were predominantly detected in MG and a few types of inner retinal neurons. In summary, NFIA and NFIB are prominently expressed in developing chick retina and by mature neurons and glia in the retinas of chicks, pigs and monkeys. Although levels of NFIs are decreased in chick, in MGPCs these levels remain higher than those seen in neurogenic RPCs. We

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

Cited by 55 publications

References 101 publications

NFkB-signaling promotes glial reactivity and suppresses Müller glia-mediated neuron regeneration in the mammalian retina

NFkB-signaling promotes glial reactivity and suppresses Müller glia-mediated neuron regeneration in the mammalian retina

Insights on the Regeneration Potential of Müller Glia in the Mammalian Retina

Nuclear Factor I in neurons, glia and during the formation of Müller glia‐derived progenitor cells in avian, porcine and primate retinas

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