BMP‐ and TGFβ‐signaling regulate the formation of Müller glia‐derived progenitor cells in the avian retina

Todd, Levi; Palazzo, Isabella; Squires, Natalie; Mendonca, Ninoshka; Fischer, Andy J.

doi:10.1002/glia.23185

Cited by 48 publications

(96 citation statements)

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“…In vitro, NF-ĸB can induce cell cycle arrest and terminal differentiation via IKKα-dependent regulation of Smad2/3 target genes (Descargues et al, 2008). We have reported that TGFβ/Smad2/3-signaling inhibits, whereas BMP4/Smad1/5/8-signaling promotes the formation of proliferating MGPCs in the chick retina (Todd et al, 2017). By contrast, the influence of NF-κB on the proliferation of MGPCs may not depend on Notch.…”

Section: Discussionmentioning

confidence: 94%

“…In NMDA-damaged retinas, microglia rapidly and transiently up-regulate IL-1α, IL-1β and TNFα , and these cytokines are known to activate NF-κB in different cells and contexts (Hayden and Ghosh, 2004;Osborn et al, 1989). In most instances the formation of MGPCs requires neuronal damage, and levels of neuronal damaged are positively correlated to numbers of proliferating MGPCs (Gallina et al, 2014b;Todd et al, 2017). However, there are examples where proliferating MGPCs form in the absence neuronal death in chick and fish model systems Fischer et al, 2009a, 20014;Wan et al, 2012;Wan et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…NF-κB-signaling is coordinated with a network of cell-signaling pathways that regulate the reprogramming of Müller glia into MGPCs. Many different cell-signaling pathways are known to participate in the formation of MGPCs in the chick retina, including MAPK (Fischer et al, 2009a;Fischer et al, 2009b), Jak/Stat Zhao et al, 2014), Notch (Ghai et al, 2010;Hayes et al, 2007), Hedgehog Wan et al, 2007), glucocorticoid (Gallina et al, 2014b), retinoic acid (Todd et al, 2018), BMP/TGFβ (Todd et al, 2017), and Wnt/β-catenin (Gallina et al, 2015). 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).…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…Conversely, Tgf-b upregulates the transcription of mmp2 (Kim et al, 2007) and mmp9 genes (Han et al, 2001), causing a positive feedback loop (Krstic and Santibanez, 2014). Despite the knowledge on the anti-proliferative involvement of Tgf-b in various model organisms (Close et al, 2005;Lenkowski et al, 2013;Todd et al, 2017), the mechanisms governed by the active Mmp/Tgf-b axis during retinal regeneration that contributes to the MG reprogramming and MGPCs induction remained unknown.…”

Section: Introductionmentioning

confidence: 99%

Biphasic Role of Tgf-β Signaling during Müller Glia Reprogramming and Retinal Regeneration in Zebrafish

et al. 2020

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“…Studies in zebrafish identified a number of genes that are rapidly induced in MG following injury and regulate neurogenic competence. Multiple extrinsic signaling pathways, including Wnt, BMP, FGF, TNFɑ, and cytokines, were found to regulate MGPC formation (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). These induce neurogenic factor genes, such as ascl1a (15) and the RNA binding protein lin28a (16), which are necessary for MG reprogramming.…”

Section: Introductionmentioning

confidence: 99%

Cross-species transcriptomic and epigenomic analysis reveals key regulators of injury response and neuronal regeneration in vertebrate retinas

Hoang

Wang

Boyd

et al. 2019

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sentence: This study identifies gene regulatory networks controlling proliferative and neurogenic competence in retinal Müller glia. AbstractInjury induces retinal Müller glia of cold-blooded, but not mammalian, vertebrates to regenerate neurons. To identify gene regulatory networks that control neuronal reprogramming in retinal glia, we comprehensively profiled injury-dependent changes in gene expression and chromatin accessibility in Müller glia from zebrafish, chick and mice using bulk RNA-Seq and ATAC-Seq, as well as single-cell RNA-Seq. Crossspecies integrative analysis of these data, together with functional validation, identified evolutionarily conserved and species-specific gene networks controlling glial quiescence, gliosis and neurogenesis. In zebrafish and chick, transition from the resting state to gliosis is essential for initiation of retinal regeneration, while in mice a dedicated network suppresses neurogenic competence and restores quiescence. Selective disruption of NFI family transcription factors, which maintain and restore quiescence, enables Müller glia to proliferate and generate neurons in adult mice following retinal injury. These findings may aid in the design of cell-based therapies aimed at restoring retinal neurons lost to degenerative disease. previously shown to induce MG reprogramming independent of injury (20). In the mouse, we also tested FGF2 and insulin treatment, which induces limited MG proliferation, but not neurogenic competence (21).For bulk RNA-Seq and ATAC-Seq, in zebrafish, we used the reporter line Tg[gfap:EGFP]nt11 (22) and cell sorting to enrich MG cells, purifying 9.8% of total input retinal cells (Fig. S1A). In mouse, we performed intraperitoneal injection of tamoxifen at postnatal day (P) 21 to induce MG-specific Sun1-GFP expression in GlastCreERT2;CAG-lsl-Sun1-GFP mice (23), purifying 3.5% of total input cells ( Fig. S1A). Based on RT-qPCR, we had an overall enrichment of 30-fold of canonical MG marker genes such as rlbp1a/Rlbp1 and Glul in the GFP-positive (GFP+) fraction in both species (Fig. S1B). Bulk RNA-Seq samples were generated from both the GFP+ MG and GFP-neuronal fractions in zebrafish and mouse, while ATAC-Seq samples were generated from the GFP+ cells. Each sample had a minimum of two biological replicates. In both species, we analyzed retinas with a time course following either inner retinal injury induced by NMDA excitotoxicity or outer retinal injury induced by light damage. In total, we generated 100 bulk RNA-Seq libraries and 40 bulk ATAC-Seq libraries ( Fig. 1A, Table S1, Supplementary Data 1).In parallel, we conducted scRNA-Seq analysis of whole retinas at the same time points as used for the bulk RNA-Seq. We profiled retinas following either NMDA or light damage in zebrafish and mouse, as well as following NMDA damage in P10 chick. To distinguish injury-responsive genes from injury-independent reprogramming genes, we profiled zebrafish retinas at multiple time points following T+R treatment, and a single time point in chick and mouse retinas...

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BMP‐ and TGFβ‐signaling regulate the formation of Müller glia‐derived progenitor cells in the avian retina

Cited by 48 publications

References 67 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

Biphasic Role of Tgf-β Signaling during Müller Glia Reprogramming and Retinal Regeneration in Zebrafish

Cross-species transcriptomic and epigenomic analysis reveals key regulators of injury response and neuronal regeneration in vertebrate retinas

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