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:10.1101/724260

Cited by 16 publications

(68 citation statements)

References 85 publications

(123 reference statements)

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“…This is unique because many signaling pathways that have been implicated in regulating the formation of MGPCs in the chick retina are active following NMDA-induced damage and treatment with insulin and FGF2. These pathways include MAPK (Fischer et al, 2009a;Fischer et al, 2009b), mTOR (Zelinka et al, 2016), Notch (Ghai et al, 2010Hayes et al, 2007), Jak/Stat (Todd et al, 2016), Wnt/b-catenin (Gallina et al, 2015), glucocorticoid (Gallina, 2015), Hedgehog (Todd and Fischer, 2015), BMP/SMAD (Todd et al, 2017), retinoic acid (Todd et al, 2018) and NFkB-signaling (Palazzo et al, 2020).…”

Section: Mdk-signaling In Mgmentioning

confidence: 99%

Midkine in chick and mouse retinas: neuroprotection, glial reactivity and the formation of Müller glia-derived progenitor cells

Campbell

Fritsch-Kelleher

Palazzo

et al. 2020

Preprint

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Recent studies have shown that midkine (MDK), a basic heparin-binding growth factor, is involved in the development and regeneration of the zebrafish retina. However, very little is known about MDK in the retinas of warm-blooded vertebrates. We investigate the expression patterns of MDK and related factors, roles in neuronal survival, and influence upon the formation of Müller glia-derived progenitor cells (MGPCs) in chick and mouse model systems. By using single-cell RNA-sequencing (scRNA-seq), we find that MDK and related factors are dynamically expressed by maturing MG and by MG in retinas damaged by NMDA or treated with insulin and FGF2. Interestingly, MDK is significantly up-regulated by MG in damaged chick retinas, but down-regulated by MG in damaged mouse retinas. In both chick and mouse retinas, exogenous MDK selectively up-regulates cFOS and pS6 (a readout of mTOR-signaling) in Müller glia. In the chick, intraocular injections of MDK before injury decrease numbers of dying cells, decrease microglial reactivity, decrease the accumulation of Non-astrocytic Inner Retinal Glial (NIRG) cells, and decrease numbers of proliferating MGPCs. Addition of MDK signaling inhibitor Na3VO4 following retinal injury reverses these effects to increase the number of dying cells, accumulation of NIRG cells, and decrease the number of proliferating MGPCs. Inhibitors of PP2A and Pak1 had specific inhibitory effects on MGPC formation. In mice, MDK administration with NMDA damage drives a small but significant increase in MGPCs. We conclude that MDK expression is dynamically regulated in reactive Müller glia and during reprogramming into MGPCs. MDK acts to coordinate glial activity, neuronal survival, and may act in an autocrine manner to influence the re-programming of Müller glia into proliferating MGPCs.

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Section: Mdk-signaling In Mgmentioning

confidence: 99%

Midkine in chick and mouse retinas: neuroprotection, glial reactivity and the formation of Müller glia-derived progenitor cells

Campbell

Fritsch-Kelleher

Palazzo

et al. 2020

Preprint

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“…Recently, two articles have been published using single cell RNA sequence (scRNA‐seq) during the reprogramming of Müller glia (Campbell et al, ; Palazzo, Deistler, Hoang, Blackshaw, & Fischer, ). Using the database published by the Authors (the same RNA database in both articles) we note that PDLIM1 is present in activated Müller cells in chicken retinas.…”

Section: Discussionmentioning

confidence: 99%

The role of PDLIM1, a PDZ‐LIM domain protein, at the ribbon synapses in the chicken retina

Rı́os

Paganelli

Fosser

2020

J of Comparative Neurology

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PDLIM's protein family is involved in the rearrangement of the actin cytoskeleton. In the present study, we describe the localization of PDLIM1 in chicken photoreceptors.This study provides evidence that this protein is present at the cone pedicles, as well as in other synapses of the chicken retina. Here, we demonstrate the expression pattern of PDLIM1 through immunofluorescence staining, immunoblots, subcellular fractionation, and immunoprecipitation experiments. Also, we consider the possibility that PDLIM1 may be involved in the synaptic vesicle endocytosis and/or the presynaptic trafficking of synaptic vesicles back to the nonready releasable pool. This endocytotic/exocytotic coupling requires a tight link between exocytic vesicle fusion at defined release sites and endocytic retrieval of synaptic vesicle membranes. In turn, photoreceptor ribbon synaptic structure depends on the cytoskeleton arrangement, both at the active zone-related with exocytosis-as well as at the endocytic zoneperiactive zone. To our knowledge, the PDLIM1 protein has not been observed in the pre synapses of the retina. Thus, the present study describes the expression and subcellular localization of PDLIM1 for the first time, as well as its modulation by visual environment in the chicken retina. K E Y W O R D SPDLIM1, PDZ and Lim protein 1, photoreceptors, retina, ribbon synapses, RRID:

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“…NF-kB is a transcription factor known to be a primary transductor of the innate and adaptive immunity, and a central mediator of inflammatory responses to pathogens or tissue damage (Liu et al, 2017). In the chick, activation or inhibition of the NF-kB pathway has a significant impact on the ability of MG to become proliferating MGPCs (Palazzo et al, 2020). In the mouse retina, NF-kB-signaling has been implicated a signaling "hub" that may act to drive MG into a reactive state and then back into a resting state (Hoang et al, 2020).…”

Section: Nf-kb Activation Is Reduced In Mouse Mg When Promoting Ecb Smentioning

confidence: 99%

“…In the chick, by comparison, TNF alone does not induce MGPCs and activation of the NF-kB pathway inhibits the formation of MGPCs (Hoang et al, 2020;Palazzo et al, 2020). When microglia are ablated, MGPCs fail to form (Fischer et al, 2014), and the effects of NF-kB-inhibition are reversed to promote the formation of MGPCs (Palazzo et al, 2020). In damaged mouse retinas, reactive MG rapidly transition into a gliotic state and are forced back into a resting state, in part, by regulatory networks involving NF-kB-related factors (Hoang et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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

Blum

Reske

et al. 2021

Preprint

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

Cited by 16 publications

References 85 publications

Midkine in chick and mouse retinas: neuroprotection, glial reactivity and the formation of Müller glia-derived progenitor cells

Midkine in chick and mouse retinas: neuroprotection, glial reactivity and the formation of Müller glia-derived progenitor cells

The role of PDLIM1, a PDZ‐LIM domain protein, at the ribbon synapses in the chicken retina

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

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