Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA196494 | ENA |
REPOSITORIES: ENA
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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: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
2013-04-06 | GSE45835 | GEO
Project description:Müller glia can serve as a source for retinal regeneration in some non-mammalian vertebrates. Recently we found that this process can be induced in mouse Müller glia after injury, by combining transgenic expression of the proneural transcription factor Ascl1 and the HDAC inhibitor TSA. However, new neurons are only generated from a subset of Müller glia in this model, and identifying factors that limit Ascl1-mediated MG reprogramming could potentially make this process more efficient, and potentially useful clinically. One factor that limits neurogenesis in some non-mammalian vertebrates is the STAT pathway activation that occurs in Müller glia in response to injury. In this report, we tested whether injury induced STAT activation hampers the ability of Ascl1 to reprogram Müller glia into retinal neurons. Using a STAT inhibitor, in combination with our previously described reprogramming paradigm, we found a large increase in the ability of Müller glia to generate neurons, similar to those we described previously. Single-cell RNA-seq showed that the progenitor-like cells derived from Ascl1-expressing Müller glia have a higher level of STAT signaling than those that become neurons. Using Ascl1 ChIP-seq and DNase-seq, we found that developmentally inappropriate Ascl1 binding sites (that were unique to the overexpression context) had enrichment for the STAT binding motif. This study provides evidence that STAT pathway activation reduces the efficiency of Ascl1-mediated reprogramming in Müller glia, potentially by directing Ascl1 to developmentally inappropriate targets.
2019-11-01 | GSE135414 | GEO
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.
2017-02-11 | GSE94759 | GEO
Project description:The innate immune system plays key roles in tissue regeneration. For example, microglia promote neurogenesis in Müller glia in birds and fish after injury. Although mammalian retina does not normally regenerate, neurogenesis can be induced in mouse Müller glia by Ascl1, a proneural transcription factor. We show that in mice, microglia inhibit the Ascl1-mediated retinal regeneration, suggesting the innate immune system limits the regenerative response to injury.
2020-12-30 | GSE161394 | GEO
Project description:In the lesioned zebrafish retina, Müller glia produce multipotent retinal progenitors that generate all retinal neurons, replacing lost cell types. To study the molecular mechanisms linking Müller glia reactivity to progenitor production and neuronal differentiation, we used single cell RNA sequencing of Müller glia, progenitors and regenerated progeny from uninjured and light-lesioned retinae. We discover an injury-induced Müller glia differentiation trajectory that leads into a cell population with a hybrid identity expressing marker genes of Müller glia and progenitors. A glial self-renewal and a neurogenic trajectory depart from the hybrid cell population. We further observe that neurogenic progenitors progressively differentiate to generate retinal ganglion cells first and bipolar cells last, similar to the events observed during retinal development. Our work provides a comprehensive description of Müller glia and progenitor transcriptional changes and fate decisions in the regenerating retina, which are key to tailor cell differentiation and replacement therapies for retinal dystrophies in humans.
2023-03-03 | GSE226373 | GEO
Project description:Following acute retinal damage, zebrafish possess the ability to regenerate all neuronal subtypes. This regeneration requires Müller glia (MG) to reprogram and divide asymmetrically to produce a multipotent Müller glia-derived neuronal progenitor cell (MGPC). This raises three key questions. First, does loss of different retinal cell subtypes induce unique MG regeneration responses? Second, do MG reprogram to a developmental retinal progenitor cell state? And finally, to what extent does regeneration recapitulate retinal development? We examined these questions by performing single-nuclear and single-cell RNA-Seq and ATAC-Seq in both developing and regenerating retinas. While MG reprogram to a state similar to late-stage retinal progenitors in developing retinas, there are transcriptional differences between reprogrammed MG/MGPCs and late progenitors, as well as reprogrammed MG in outer and inner retinal damage models. Validation of candidate genes confirmed that loss of different subtypes induces differences in transcription factor gene expression and regeneration outcomes. This work identifies major differences between gene regulatory networks activated following the selective loss of different subtypes of retina neurons, as well as between retinal regeneration and development.
2023-08-31 | GSE239410 | GEO
Project description:Regeneration of neurons has enormous implications for human health and is a topic of interest both from the biological and translational perspective. The retina poses an excellent system to study the potential of replacing neurons following injury and the impact different lesions can have on this process. We have established mouse models where proneural transcription factors are expressed in Müller glia to stimulate neurogenesis, which is analogous to how zebrafish regenerate the retina after injury. Our previous studies have shown that Müller glia overexpressing either Ascl1 or Ascl1-Atoh1 will respond to inner retinal damage, caused by a neurotoxic dose of NMDA, by acquiring a progenitor-like state and giving rise to bipolar cells or retinal ganglion-like cells, respectively. It was not known however whether neurogenesis would still occur if the retina suffered outer retinal injury and if the timing of injury relative to the expression of proneural factors was critical for the process. To address these questions, we explored whether timing or mode of injury affect the induced neurogenesis from MG. We show that reprogramming MG with Ascl1 is not impacted by the mode or timing of injury, since all paradigms resulted in similar ratios of new bipolar neurons. By contrast, MG that express Ascl1-Atoh1 respond to outer retinal damage by producing a new type of retinal ganglion-like cell that is not generated after NMDA injury. Therefore, although the fate of reprogrammed neurons is mostly dictated by the proneural transcription factors, there is a context-dependent effect of the injured retinal microenvironment.
2023-12-13 | GSE250019 | GEO
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.
2020-12-24 | GSE162993 | GEO
Project description:In order to identify the miRNAs in adult Dicer1-CKO Müller glia of the neural retina, we isolated the Müller glia from Rlbp-CreER: Stopf/f-tdTomato/Dicerf/f mice by means of fluorescent activated cell sorting and analyzed their miRNAs using NanoStrings Technologies®. miRNA expression of Dicer1-CKO Müller glia was compared to wild type Müller glia (a re-analyzed sample from GSE94759). We found that all highly expressed miRNAs declined in the Dicer-CKO leading to a disruption in retinal architecture over time.
2017-10-31 | GSE103098 | GEO