Transcriptome and DNA methylome of mouse Müller glia
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE124532 | GEO | 2019/11/12
REPOSITORIES: GEO
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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: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: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:We found that the zebrafish non-coding element careg, which is induced in regenerating fins and heart, also participates in retina regeneration. Its activation persisted mostly in Müller glia from the onset to the termination of retina restoration. To assess the involvement of the careg:EGFP reporter during retina regeneration, we used a chemical injury model with MNU treatment. To identify the molecular profile of these cells, we performed a single-cell RNA sequencing (scRNA-seq) experiment of retinas dissected from adult careg:EGFP zebrafish at 3, 7, and 10 dpMNU. Our control retinas were dissected from fish at 3 days after treatment with heat-inactivated MNU
2023-05-10 | GSE202212 | GEO
Project description:Müller glial cells (MG) generate retinal progenitor (RPC)-like cells after injury in non-mammalian species, though this does not occur in the mammalian retina. Studies have profiled gene expression in these cells to define genes that may be relevant to their differences in neurogenic potential. However, less is known about differences in micro-RNA (miRNA) expression. In this study, we compared miRNAs from RPCs and MG to identify miRNAs more highly expressed in RPCs, and others more highly expressed in MG. To determine whether these miRNAs are relevant to the difference in neurogenic potential between these two cell types, we tested them in dissociated cultures of MG using either mimics or antagomiRs to increase or reduce expression, respectively. Among the miRNAs tested, miR-25 and miR-124 over-expression, or let-7 antagonism, induced Ascl1 expression and conversion of approximately 40% of mature MG into a neuronal/RPC phenotype. Our results suggest that the differences in miRNA expression between MG and RPCs contribute to their difference in neurogenic potential and that manipulations in miRNAs provide a new tool to reprogram MG for retinal regeneration.
2019-08-14 | GSE135816 | GEO
Project description:Background: Adult zebrafish spontaneously regenerate their retinas after damage. Although a number of genes and signaling pathways involved in regeneration have been identified, the extent of mechanisms regulating regeneration is unclear. Small non-coding RNAs, microRNAs (miRNAs), that regulate regeneration of various tissues in lower vertebrates were examined for their potential roles in regulating zebrafish retinal regeneration. Results: To investigate the requirement of miRNAs during zebrafish retinal regeneration, we knocked down the expression of the miRNA-processing enzyme Dicer in retinas prior to light-induced damage. Dicer loss significantly reduced proliferation of Müller glia-derived neuronal progenitor cells during regeneration. To identify individual miRNAs with roles in retina regeneration, we collected retinas at different stages of light damage and performed small RNA high-throughput sequencing. We identified subsets of miRNAs that were differentially expressed during active regeneration but returned to basal levels once regeneration was completed. To validate the roles of differentially expressed miRNAs, we knocked down 6 different miRNAs that were upregulated in expression during regeneration and demonstrated that they have distinct effects on neuronal progenitor cell proliferation and migration during retina regeneration. Conclusions: miRNAs are necessary for retinal regeneration. miRNA expression is dynamic during regeneration. miRNAs function during initiation and progression of retinal regeneration. Identification of miRNAs before, during and after completion of zebrafish retinal regeneration
2014-09-20 | E-GEOD-58702 | biostudies-arrayexpress
Project description:This study has applied proteomic methodologies to compare protein expression profiles of gliotic and normal human retina as well as established human Müller stem cell lines. It is hoped that this investigation may provide insight into mechanisms of gliosis and also aid studies focusing on endogenous regeneration of the retina following disease or injury
2018-09-06 | PXD008485 | Pride
Project description:Contrasting with fish or amphibian, retinal regeneration from Müller glial cells is largely limited in mammals. In our quest towards the identification of molecular cues that may boost their stemness potential, we investigated the involvement of the Hippo pathway effector YAP, which we previously found to be upregulated in Müller cells following retinal injury. We report that conditional Yap deletion in Müller cells prevents the upregulation of cell cycle genes that normally accompanies reactive gliosis upon photoreceptor cell death. This occurs as a consequence of defective EGFR signaling. Consistent with a function of YAP in triggering Müller glia cell cycle re-entry, we further show that in Xenopus, a species endowed with efficient regenerative capacity, YAP is required for their injury-dependent proliferative response. Finally, and noteworthy, we reveal that YAP overactivation in mouse Müller cells is sufficient to induce their reprogramming into highly proliferative cells. Overall, we unravel a pivotal role for YAP in tuning Müller cell response to injury and highlight a novel YAP-EGFR axis by which Müller cells exit their quiescence state, a critical step towards regeneration.
2019-06-01 | GSE121858 | 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.
2023-08-21 | GSE218107 | GEO
Project description:Many retinal diseases lead to the loss of retinal neurons and cause visual impairment. The adult mammalian retina has little capacity for regeneration. By contrast, teleost fish functionally regenerate their retina following injury, and Müller glia (MG) are the source of regenerated neurons. The proneural transcription factor Ascl1 is upregulated in MG after retinal damage in zebrafish and is necessary for regeneration. Although Ascl1 is not expressed in mammalian MG after injury, forced expression of Ascl1 in mouse MG induces a neurogenic state in vitro and in vivo after NMDA (N-methyl-d-aspartate) damage in young mice. However, by postnatal day 16, mouse MG lose neurogenic capacity, despite Ascl1 overexpression. Loss of neurogenic capacity in mature MG is accompanied by reduced chromatin accessibility, suggesting that epigenetic factors limit regeneration. Here we show that MG-specific overexpression of Ascl1, together with a histone deacetylase inhibitor, enables adult mice to generate neurons from MG after retinal injury. The MG-derived neurons express markers of inner retinal neurons, synapse with host retinal neurons, and respond to light. Using an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), we show that the histone deacetylase inhibitor promotes accessibility at key gene loci in the MG, and allows more effective reprogramming. Our results thus provide a new approach for the treatment of blinding retinal diseases.
2021-01-10 | GSE164489 | GEO