Müller glial microRNAs are required for the maintenance of glial homeostasis and retinal architecture
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE103098 | GEO | 2017/10/31
SECONDARY ACCESSION(S): PRJNA400179
REPOSITORIES: GEO
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Project description:In order to identify the miRNAs in adult light damaged Muller glia of the the neural retina, we isolated the Müller glia from Rlbp-CreER: Stopf/f-tdTomato by means of fluorescent activated cell sorting and analyzed their miRNAs using NanoStrings Technologies®. We compared the data to that from and Dicer1-CKO Müller glia and wild type glia Müller glia (GSE103098). We found three miRNAs potentially regulating genes involved in stress response in both data sets.
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Project description:In order to identify the miRNAs in adult and young (postnatal day 11/12) Müller glia of the neural retina, we isolated the Müller glia from Rlbp-CreER: Stopf/f-tdTomato mice by means of fluorescent activated cell sorting and analyzed their miRNAs using NanoStrings Technologies®. We next compared miRNA expression of acutely isolated Müller glia with those that were maintained in dissociated culture for 8 and 14 days. We found that most miRNAs declined in vitro. Interestingly, some miRNAs that were not highly expressed in adult Müller glia increased in cultured cells. Our results thus show the miRNA profile of adult Müller glia and the effects of cell culture on their levels.
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Project description:In order to identify the miRNAs in postnatal day 2 (P2) retinal progenitor cells (RPCs), and P8, P11, and adult Müller glia (MG) of the neural retina, we isolated the retinal progenitors from Sox2-CreER: Stopf/f-tdTomato and MG from Rlbp-CreER: Stopf/f-tdTomato mice by means of fluorescent activated cell sorting and analyzed their miRNAs using NanoStrings Technologies®. We next compared miRNA expression of RPCs with MG. We found that most specific miRNAs decline with glial maturation (RPC miRNAs) while others increase (MG miRNAs). Overexpression of miRNA-25 found in RPCs and inhibition of MG miRNA let-7 can induce a neurogenic potential in MG and initiates a de novo differentiation toward neuronal fates.
2019-08-14 | GSE135835 | GEO
Project description:In order to identify the mRNAs in adult light damaged Muller glia of the the neural retina, Müller glia from Hes-5 GFP reporter mice that were crossed with Swiss Webster mice were isolated by means of fluorescent activated cell sorting and analyzed their mRNAs using the Mouse Gene 1.0 ST microarray (Affymetrix). Differentially expressed genes were analyzed and compared to the genes found upregulated in the Dicer-cKO mouse (Wohl at el., 2017). miRNA:mRNA target tools were used to find potential miRNA targets of Muller glia miRNAs.
2020-12-24 | GSE163753 | GEO
Project description:Purpose: Zebrafish neurons regenerate from Müller glia following retinal lesions. Genes and signaling pathways important for retinal regeneration in zebrafish have been described, but our understanding of how Müller glial stem cell properties are regulated is incomplete. Mammalian Müller glia possess a latent neurogenic capacity that might be enhanced in regenerative therapies to treat degenerative retinal diseases. Methods: To identify transcriptional changes associated with stem cell properties in zebrafish Müller glia, we performed a comparative transcriptome analysis from isolated cells at 8 and 16 hours following an acute, photic lesion, prior to the asymmetric division that produces retinal progenitors. Results: We report a rapid, dynamic response of zebrafish Müller glia, characterized by activation of pathways related to stress, NF-kappa B signaling, cytokine signaling, immunity, prostaglandin metabolism, circadian rhythm, and pluripotency, and an initial repression of Wnt signaling. When we compared publicly available transcriptomes of isolated mouse Müller glia from two retinal degeneration models, we found that mouse Müller glia showed evidence of oxidative stress, variable responses associated with immune regulation, and repression of pathways associated with pluripotency, development, and proliferation. Conclusions: Categories of biological processes/pathways activated following photoreceptor loss in regeneration-competent zebrafish Müller glia, which distinguished them from mouse Müller glia in retinal degeneration models, included: cytokine signaling (notably NF-kappa B), prostaglandin E2 synthesis, expression of core clock genes, and pathways/metabolic states associated with pluripotency. These regulatory mechanisms are relatively unexplored as potential mediators of stem cell properties likely to be important in Müller glial cells for successful retinal regeneration.
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Project description:As any other radial glia in the central nervous system, Müller glia derive from the same neuroepithelial precursors, perform similar functions and exhibit neurogenic properties as radial glia in the brain. Müller glial cells retain progenitor-like characteristics in the adult human eye, and can partially restore visual function upon intravitreal transplantation into animal models of glaucoma. Recently, it has been demonstrated that intracellular communication is possible via the secretion of nano-sized membrane-bound extracellular vesicles (EV), which contain bioactive molecules like microRNA (miRNA) and proteins that induce phenotypic changes when internalised by recipient cells. We conducted high-throughput sequencing to profile the microRNA signature of EV populations secreted by Müller glia in culture, and used bioinformatic tools to evaluate their potential role in the neuroprotective signalling attributed to these cells. Sequencing of miRNA within Müller EV suggested enrichment with species associated with stem cells such as miR-21 and miR-16, as well as with miRNA previously found to play a role in diverse Müller cell functions in the retina: miR-9, miR-125b and the let-7 family. A total of 51 miRNA were found to be differentially enriched in EV compared to whole cells from which EV originated. Bioinformatic analyses also indicated preferential enrichment of species demonstrated to regulate genes involved in cell proliferation and survival, including PTEN the master inhibitor of the PI3K/AKT pathway. The results suggest that the release by Müller cells of miRNA-enriched EV abundant in species that regulate anti-apoptotic signalling networks, is likely to represent a significant proportion of the neuroprotective effect observed after transplantation of these cells into animal models of retinal ganglion cell (RGC)-depletion. Future work will seek to evaluate the modulation of putative genes, as well as the activation of these pathways in in vitro and in vivo models following the internalisation of Müller-EV by target retinal neurons.
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Project description:Non-mammalian vertebrates have a robust ability to regenerate injured retinal neurons from Müller glia cells (MG) that activate the proneural factor Achaete-scute homolog 1 (Ascl1/Mash1) and de-differentiate into progenitors cells. In contrast, mammalian MG have a limited regenerative response and fail to upregulate Ascl1 after injury. To test whether Ascl1 could restore a neurogenic potential to mammalian MG, we over-expressed Ascl1 in dissociated mouse MG cultures and intact retinal explants. Ascl1-infected MG upregulate retinal progenitor-specific genes, while downregulating glial genes. Furthermore, Ascl1 remodeled the chromatin at its targets from a repressive to active configuration. MG-derived progenitors differentiated into cells that exhibited neuronal morphologies, expressed retinal subtype-specific neuronal markers, and displayed neuron-like physiological responses. These results indicate that a single transcription factor, Ascl1, can produce a neurogenic state in mature Muller glia. Expresssion profiling was used to determine the genes that were changed after Ascl1 infection of P12 cultured Müller glia compared with those present in P0 progenitors and P7-P21 Müller glia Retinas were dissociated and FAC-sorted from Hes5-GFP mice at P0, P7, P10, P14 or P21 and submitted for profiling. WT Retinas were dissociated at P12, grown for 1 week in culture, and infected with lentiviruses expressing Ascl1 or GFP for four days. Total RNA was extracted and submitted for profiling.
2013-04-06 | E-GEOD-45835 | biostudies-arrayexpress
Project description:To study molecular changes during differentiation of retinal progenitor cells (RPCs) into Müller glia, we isolated Notch1+ cells (Notch1 is a marker of RPCs) from postnatal-day (P) 0, 3, 7, and 14 retinas,as well as Glast + cells (Glast/Slc1a3 is a marker of Müller glia precursors and Müller glia in the retina) from P7, P14, P21, and P28 retinas. We studied gene expression in these cells using MEEBO microarrays.
2019-07-23 | GSE122301 | GEO
Project description:Loss of neurons in the neural retina is a leading cause of vision loss. Retinal regeneration in zebrafish is attributed to Müller glia, which are activated, adopt a stem cell-like state, proliferate, and generate new neurons. Despite the same endogenous Müller glia being present in all vertebrates including humans, Müller glia activation in mammals leads to glial scarring instead of neurogenesis. Therefore, understanding Müller glia cellular states and molecular processes during zebrafish regeneration may allow us to improve mammalian regeneration. Since only a subset of Müller glia activate following neuron loss, we asked whether a specialised subset of Müller glia might be genetically primed for activation. Single-cell RNA sequencing (sc-RNAseq) from integrated zebrafish Müller glia samples reveals heterogeneity of gene expression across the quiescent Müller glia pool with 4 main clusters emerging, two of which are genetically similar. Labelling for key differentially expressed markers identified that these main clusters correlated with glia spatially distributed across dorsal, central and ventral retina. Using a genetically driven, chemically induced nitroreductase approach, three distinct photoreceptor types were ablated: the long (Lws2), short wavelength-sensitive (Sws2) and rod (Xops) photoreceptors, which also differ in their abundance. As expected, histological analysis of the three injuries and sc-RNAseq data for the two cone photoreceptor ablations identified common genetic program involved in the transition of Müller glia quiescence to activation, and differential responses to injury related to either injury extent or subtype of photoreceptor targeted. Interestingly, despite differences in the distributed across the retina, biased activation of Müller glia was observed in dorsal and central regions. Gene ontology analysis revealed that these injury-responsive dorsal and central Müller glia express genes related to dorsal/ventral pattern formation, growth factor activity, and regulation of developmental process. Müller glia upregulated genes related to homeostasis as well as certain AP-1 and injury-responsive transcription factors, followed by expression of genes involved in cell cycle, chromatin remodeling, and microtubule organisation. Prior to cell cycle entry, Müller glia show a transient upregulation of genes involved in gliogenesis, and Notch signalling. These findings enhance our understanding of heterogeneous states of quiescent Müller glia, and how these differences relate to activation and regeneration potential following neural ablation. A comparison of the distinct quiescent Müller glia with glia states in mammals will reveal key molecular pathways that could be targeted for improved mammalian neural regeneration.
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