The Hippo Pathway Blocks Mammalian Retinal Müller Glial Cell Reprogramming
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ABSTRACT:
PROVIDER: PRJNA498120 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8099200_1.fastq.gz | Fastqsanger.gz | |||
| SRR8099200_2.fastq.gz | Fastqsanger.gz | |||
| SRR8099201_1.fastq.gz | Fastqsanger.gz | |||
| SRR8099201_2.fastq.gz | Fastqsanger.gz | |||
| SRR8099202_1.fastq.gz | Fastqsanger.gz |
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Project description:Müller glial cells (MGs) of the zebrafish retina exhibit the remarkable ability to reprogram to proliferative, retinal progenitor-like cells that can regenerate lost photoreceptors and restore vision. Unfortunately, mammalian MGs are not regenerative and this is at least in part due to the inability of MGs to undergo sustained cell cycle re-entry in response to retinal damage. Here, we identify the Hippo pathway as the core regulatory mechanism that normally prevents mammalian MG reprogramming to a proliferative, progenitor-like state. Specifically, in adult MGs within the damaged retina, Hippo signaling represses the activity of the transcription cofactor YAP, which would otherwise promote sustained MG cell cycle re-entry. MG-specific deletion of Hippo pathway components Lats1 and Lats2 resulted in Cyclin D1 upregulation and spontaneous MG proliferation. These data suggest that sustained YAP activity in reactive MGs induces MG proliferation and reprogramming, but this response is normally repressed by the Hippo pathway. Generation of MGs that express a variant of YAP (YAP5SA) that is non-responsive to Hippo signaling, resulted in cellular reprogramming whereby MG identity was lost and the cells acquired a highly proliferative, progenitor-like state. Together, our results reveal that MGs may have latent regenerative capacity that can be “reawakened” by blocking Hippo signaling.
2019-05-07 | GSE121707 | GEO
Project description:Rat Retinal Müller cells from diabetic rats (diabetes duration 6 months) compared to Rat Retinal Müller cells from healthy rats. Diabetes was induced by streptozotozine. Diabetic rats were treated with small doses of insulin to prevent catabolism. Keywords: ordered
2004-11-17 | E-GEOD-1979 | biostudies-arrayexpress
Project description:Small extracellular vesicles (sEVs) are critical for cell-to-cell communication in retinal health and disease. This study aims to characterize the proteome of sEVs derived from human retinal Müller glial cells under normal glucose and high glucose conditions to understand their role in diabetic retinopathy. We performed high-resolution proteomic analyses on sEVs and their parent retinal Müller glial cells under both normal glucose and high glucose conditions. Comprehensive bioinformatics analyses, including gene ontology and protein-protein interaction network analyses, were conducted to assess the biological processes, molecular functions, cellular components, and signaling pathways associated with differentially expressed proteins. Additionally, physical attributes of sEVs, such as particle size, concentration, and morphology, were evaluated. Our analysis revealed no significant differences in the physical attributes of sEVs between normal glucose and high glucose conditions. However, proteomic analysis identified substantial alterations in the protein composition of sEVs under high glucose conditions. Differentially expressed proteins included common sEV proteins as well as cell-specific proteins. Gene ontology analysis highlighted enriched biological processes, molecular functions, cellular components, and signaling pathways associated with these differentially expressed proteins. Protein-protein interaction network analysis illustrated the interaction networks of differentially expressed proteins and identified specific functional modules within these networks. The main conclusions are that sEVs derived from retinal Müller glial cells transmit altered protein constituents under diabetic conditions, contributing to the pathogenesis of diabetic retinopathy.
2025-09-11 | PXD057318 | Pride
Project description:Purpose. Immune privilege in the eye is a compilation of anti-inflammatory mechanisms that protect vision from the damaging sequelae of intense immune responses. Although the breakdown of privilege can lead to ocular disease, little is known about how these mechanisms are regulated. Since retinal Müller glial cells and autophagy also have anti-inflammatory properties, we tested the idea that Müller cells utilize autophagy to support immune privilege. Methods. The essential autophagy regulator Atg5 was deleted in retinal Muller cells using a tamoxifen inducible GlastCre ERT X Atg5f/f strain. Intraocular inflammation was induced by intravitreal injection of LPS and monitored by H&E staining, immunofluorescent confocal microscopy, and flow cytometry. scRNA-seq was performed on retinal Müller cells isolated from control and Atg5-deficient mice. Additionally, markers of Müller cell gliosis and function were assessed by western blotting and cytokines were detected by Luminex cytokine/chemokine arrays. In cultured Müller cells siRNA knockdown techniques were used to examine the role of autophagy in regulation of LPS-induced inflammatory pathways. Results. We observed increased and prolonged intraocular inflammation when Müller cells were autophagy (Atg5) deficient. Müller cell gliosis (as measured by Gfap expression) was significantly increased and inflammation was sustained over 5 days post-LPS injection compared to control. The retinae with Atg5-deficient Müller cells also contained increased inflammatory mediators and neuroprotective molecules. Gene expression analysis revealed a heterogeneous response to LPS in Müller glial cell population that revealed 2 states of activation. The normal retinae contain Müller cells in both a basal and an activated state, while autophagy deficient retinae (Atg5iΔMüller) contained only activated Müller cells. Analysis of gliosis markers Gfap and Lcn2 confirmed this heterogeneity showing that in control eyes basal and activated (gliotic) Müller glia were observed; however, with autophagy deficiency nearly all Müller cells were gliotic. Interestingly, activated cells were largely indistinguishable between autophagy sufficient and deficient Müller cells. In cultured Müller cells, siRNA knockdown of autophagy genes resulted in heightened mTOR activation, increased Gfap expression, and upregulated cytokine/chemokine production. Conclusions. Autophagy deficiency in Müller cells leads to enhanced intraocular inflammation though activation of the mTOR pathway. Our data suggests that autophagy defines a novel perspective on Müller glial heterogeneity based on their activation state. Thus, autophagy restrains cellular activation and inflammation, supporting immune privilege by preventing excessive and potentially destructive immune responses.
2025-09-10 | GSE293132 | 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
Project description:PURPOSE. During retinal degeneration, Müller glia cells respond to photoreceptor loss by undergoing reactive gliosis, with both detrimental and beneficial effects. Increasing our knowledge of the complex molecular response of Müller cells to retinal degeneration is thus essential for the development of new therapeutic strategies. The purpose of this work was to identify new factors involved in Müller cell response to photoreceptor cell death. METHODS. Whole transcriptome sequencing was performed from wild-type and degenerating rd10 mouse retinas at P30. The changes in mRNA abundance for several deregulated genes were assessed by RT-qPCR. Protein expression level and retinal cellular localization were determined by western-blot and immunohistochemistry, respectively. RESULTS. Pathway-level analysis from whole transcriptomic data revealed the Hippo/YAP pathway as one of the main signaling pathways altered in response to photoreceptor degeneration in rd10 retinas. We found that downstream effectors of this pathway, YAP and TEAD1, are specifically expressed in Müller cells and that their expression, at both the mRNA and protein levels, is increased in rd10 reactive Müller glia after the onset of photoreceptor degeneration. The expression of Ctgf and Cyr61, two target genes of the transcriptional YAP/TEAD complex, is also upregulated following photoreceptor loss. CONCLUSIONS. This work reveals for the first time that YAP and TEAD1, key downstream effectors of the Hippo pathway, are specifically expressed in Müller cells. We also uncovered a deregulation of the expression and activity of Hippo/YAP pathway components in reactive Müller cells under pathological conditions.
2017-05-29 | GSE94534 | 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.
2016-09-14 | GSE86872 | 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:Rat Retinal Müller cells from diabetic rats (diabetes duration 6 months) compared to Rat Retinal Müller cells from healthy rats. Diabetes was induced by streptozotozine. Diabetic rats were treated with small doses of insulin to prevent catabolism. Keywords: ordered
2004-11-17 | GSE1979 | GEO
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