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

2021 ◽  
Author(s):  
Isabella Palazzo ◽  
Levi J. Todd ◽  
Thanh V. Hoang ◽  
Thomas A. Reh ◽  
Seth Blackshaw ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Immune Cells ◽  
Muller Glia ◽  
Müller Glia ◽  
Dynamic Expression ◽  
Lower Vertebrates ◽  
Mammalian Retina ◽  
Neuron Regeneration ◽  
Glial Reactivity

AbstractMüller 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 TGFβ2 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.

scholarly journals A high-density narrow-field inhibitory retinal interneuron with direct coupling to Müller glia

2020 ◽  
Author(s):  
William N Grimes ◽  
Didem Göz Aytürk ◽  
Mrinalini Hoon ◽  
Takeshi Yoshimatsu ◽  
Clare Gamlin ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Glial Cells ◽  
Amacrine Cell ◽  
Electrical Coupling ◽  
Amacrine Cells ◽  
Muller Glia ◽  
Müller Glia ◽  
Cell Type ◽  
Mammalian Retina ◽  
Ganglion Neurons

AbstractAmacrine cells are interneurons comprising the most diverse cell type in the mammalian retina. They help encode visual features such as edges or directed motion by mediating excitatory and inhibitory interactions between input (i.e. bipolar) and output (i.e. ganglion) neurons in the inner plexiform layer (IPL). Like other brain regions, the retina also contains glial cells that contribute to neurotransmitter uptake, neurovascular control and metabolic regulation. Here, we report that a previously poorly characterized, but relatively abundant, inhibitory amacrine cell type in the mouse retina is coupled directly to Müller glia. Electron microscopic reconstructions of this amacrine type revealed extensive associations with Müller glia, whose processes often completely ensheathe the neurites of this amacrine cell type. Microinjections of small tracer molecules into the somas of these amacrine cells led to selective labelling of nearby Müller glia, leading us to suggest the name “Müller glia-coupled amacrine cell” or MAC. Our electrophysiological data also indicate that MACs release glycine at conventional chemical synapses with amacrine, bipolar and retinal ganglion cells (RGCs), and viral transsynaptic tracing showed connections to several known RGC types. Visually-evoked responses revealed a strong preference for light increments; these “ON” responses were primarily mediated by excitatory chemical synaptic input and direct electrical coupling to other cells. This initial characterization of the MAC provides the first evidence for neuron-glia coupling in the mammalian retina and identifies the MAC as a potential link between inhibitory processing and glial function.Significance StatementGap junctions between pairs of neurons or glial cells are commonly found throughout the nervous system, and play a myriad of roles including electrical coupling and metabolic exchange. In contrast, gap junctions between neurons and glia cells are rare and poorly understood. Here we report the first evidence for neuron-glia coupling in the mammalian retina, specifically between an abundant (but previously unstudied) inhibitory interneuron and Müller glia.

scholarly journals Neural stem cell properties of Müller glia in the mammalian retina: Regulation by Notch and Wnt signaling

2006 ◽  
Vol 299 (1) ◽  
pp. 283-302 ◽  
Author(s):  
Ani V. Das ◽  
Kavita B. Mallya ◽  
Xing Zhao ◽  
Faraz Ahmad ◽  
Sumitra Bhattacharya ◽  
...  
Keyword(s):  
Stem Cell ◽  
Wnt Signaling ◽  
Neural Stem Cell ◽  
Muller Glia ◽  
Müller Glia ◽  
Mammalian Retina

scholarly journals Regulation of Stem Cell Properties of Müller Glia by JAK/STAT and MAPK Signaling in the Mammalian Retina

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Krista M. Beach ◽  
Jianbo Wang ◽  
Deborah C. Otteson
Keyword(s):  
Stem Cells ◽  
Embryonic Stem ◽  
Mapk Signaling ◽  
Muller Glia ◽  
Müller Glia ◽  
Cellular Mechanisms ◽  
Blood Retinal Barrier ◽  
Extrinsic Factors ◽  
Radial Glial Cells ◽  
Mammalian Retina

In humans and other mammals, the neural retina does not spontaneously regenerate, and damage to the retina that kills retinal neurons results in permanent blindness. In contrast to embryonic stem cells, induced pluripotent stem cells, and embryonic/fetal retinal stem cells, Müller glia offer an intrinsic cellular source for regenerative strategies in the retina. Müller glia are radial glial cells within the retina that maintain retinal homeostasis, buffer ion flux associated with phototransduction, and form the blood/retinal barrier within the retina proper. In injured or degenerating retinas, Müller glia contribute to gliotic responses and scar formation but also show regenerative capabilities that vary across species. In the mammalian retina, regenerative responses achieved to date remain insufficient for potential clinical applications. Activation of JAK/STAT and MAPK signaling by CNTF, EGF, and FGFs can promote proliferation and modulate the glial/neurogenic switch. However, to achieve clinical relevance, additional intrinsic and extrinsic factors that restrict or promote regenerative responses of Müller glia in the mammalian retina must be identified. This review focuses on Müller glia and Müller glial-derived stem cells in the retina and phylogenetic differences among model vertebrate species and highlights some of the current progress towards understanding the cellular mechanisms regulating their regenerative response.

scholarly journals Midkine is neuroprotective and influences glial reactivity and the formation of Müller glia‐derived progenitor cells in chick and mouse retinas

Glia ◽  
2021 ◽  
Author(s):  
Warren A. Campbell ◽  
Amanda Fritsch‐Kelleher ◽  
Isabella Palazzo ◽  
Thanh Hoang ◽  
Seth Blackshaw ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Muller Glia ◽  
Müller Glia ◽  
Glial Reactivity

scholarly journals Efficient stimulation of retinal regeneration from Müller glia in adult mice using combinations of proneural bHLH transcription factors

Cell Reports ◽  
2021 ◽  
Vol 37 (3) ◽  
pp. 109857
Author(s):  
Levi Todd ◽  
Marcus J. Hooper ◽  
Alexandra K. Haugan ◽  
Connor Finkbeiner ◽  
Nikolas Jorstad ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Muller Glia ◽  
Müller Glia ◽  
Retinal Regeneration ◽  
Adult Mice ◽  
Bhlh Transcription Factors ◽  
Stimulation Of

scholarly journals Stimulation of Retinal Pigment Epithelium With an α7 nAChR Agonist Leads to Müller Glia Dependent Neurogenesis in the Adult Mammalian Retina

2019 ◽  
Vol 60 (2) ◽  
pp. 570 ◽  
Author(s):  
Mark K. Webster ◽  
Betty J. Barnett ◽  
Megan L. Stanchfield ◽  
Joshua R. Paris ◽  
Sarah E. Webster ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Muller Glia ◽  
Müller Glia ◽  
Α7 Nachr ◽  
Mammalian Retina ◽  
Stimulation Of

scholarly journals DNA Damage Response in Proliferating Müller Glia in the Mammalian Retina

2016 ◽  
Vol 57 (3) ◽  
pp. 1169 ◽  
Author(s):  
Kaori Nomura-Komoike ◽  
Fuminori Saitoh ◽  
Yuta Komoike ◽  
Hiroki Fujieda
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Muller Glia ◽  
Müller Glia ◽  
Damage Response ◽  
Mammalian Retina

Sonic hedgehog promotes stem-cell potential of Müller glia in the mammalian retina

2007 ◽  
Vol 363 (2) ◽  
pp. 347-354 ◽  
Author(s):  
Jin Wan ◽  
Hua Zheng ◽  
Hong-Lei Xiao ◽  
Zhen-Jue She ◽  
Guo-Min Zhou
Keyword(s):  
Stem Cell ◽  
Sonic Hedgehog ◽  
Muller Glia ◽  
Müller Glia ◽  
Cell Potential ◽  
Mammalian Retina ◽  
Stem Cell Potential

scholarly journals Cannabinoid signaling promotes the reprogramming of Muller glia into proliferating progenitor cells.

2021 ◽  
Author(s):  
Warren Campbell ◽  
Sydney Blum ◽  
Alana Reske ◽  
Thanh Hoang ◽  
Seth Blackshaw ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Expression Patterns ◽  
Synaptic Function ◽  
Muller Glia ◽  
Müller Glia ◽  
Rna Seq ◽  
Retinal Neurons ◽  
Pharmacological Agents ◽  
Retinal Microglia ◽  
Glial Reactivity

Endocannabinoids (eCB) are lipid-based neurotransmitters that are known to influence synaptic function in the visual system. eCBs are also known to suppress neuroinflammation in different pathological states. However, nothing is known about the roles of the eCB system during reprogramming of Müller glia (MG) into proliferating progenitor-like cells in the retina. Accordingly, we used the chick and mouse model to characterize expression patterns of eCB-related genes and applied pharmacological agents to examine how the eCB system impacts glial reactivity and the capacity of MG to become Müller glia-derived progenitor cells (MGPCs). We probed single cell RNA-seq libraries to identify eCB-related genes and identify cells with dynamic patterns of expression in damaged retinas. MG and inner retinal neurons expressed the eCB receptor CNR1, as well as enzymes involved in eCB metabolism. In the chick, intraocular injections of 2-Arachidonoylglycerol (2-AG) and Anandamide (AEA) potentiated the formation of MGPCs. Consistent with these findings, CNR1-agonists and MGLL-inhibitor promoted reprogramming, whereas CNR1-antagonist and inhibitors of eCB synthesis suppressed reprogramming. Surprisingly, retinal microglia were largely unaffected by increases or decreases in eCB signaling in both chick and mouse models. However, eCB-signaling suppressed the activation of NFkB-reporter in MG in damaged mouse retinas. We conclude that the eCB system in the retina influences the reactivity of MG and is important for regulating glial reactivity and the reprogramming of MG into proliferating MGPCs, but not for regulating the reactivity of immune cells in the retina.

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