The regulators of Müller glia-mediated retinal regeneration
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Zuguo Liu
PROVIDER: PXD072935 | iProX | Mon Jan 12 00:00:00 GMT 2026
REPOSITORIES: iProX
Similar Datasets
Project description:Many genes are known to regulate Müller glia (MG)-dependent retinal regeneration following widespread tissue damage. Conversely, genes controlling regeneration following limited retinal cell loss, per degenerative disease, are undefined. Studying regeneration in the context of selective cell loss is important as evidence suggests injury specifics inform the regenerative process. Here, transgenic zebrafish enabling inducible selective retinal ganglion cell (RGC) ablation were combined with single cell multiomics and CRISPR/Cas9-based knockout methods to screen 101 genes for effects on RGC regeneration. We identified 18 regulators of RGC regeneration- seven knockouts inhibited and eleven promoted RGC regeneration. Surprisingly, 35 of 36 known/implicated regulators of retinal tissue regeneration following widespread damage were not required for RGC regeneration, and seven of these knockouts actually enhanced RGC replacement kinetics, including sox2, olig2, and ascl1a. Mechanistic analyses revealed ascl1a knockout increased the propensity of progenitor cells to produce RGCs; i.e., biased progenitor cell fate. These data demonstrate plasticity in how MG can convert to a stem-like state and context-specificity in how genes function during regeneration. Increased understanding of how disease-relevant cell types can be selectively regenerated will, support the development of disease-tailored regenerative therapeutics.
2024-05-27 | GSE268179 | GEO
Project description:In the retina of adult teleosts, stem cells are sustained in two specialized niches: the ciliary marginal zone (CMZ) and the microenvironment surrounding adult Müller glia. Recently, Müller glia were identified as the regenerative stem cells in the teleost retina. Secreted signaling molecules that regulate neuronal regeneration in the retina are largely unknown. In a microarray screen to discover such factors, we identified midkine-b (mdkb). Midkine is a highly conserved heparin-binding growth factor with numerous biological functions. The zebrafish genome encodes two distinct midkine genes: mdka and mdkb. Here, we describe the cellular expression of mdka and mdkb during retinal development and the initial, proliferative phase of photoreceptor regeneration. The results show that in the embryonic and larval retina mdka and mdkb are expressed in stem cells, retinal progenitors and neurons in distinct patterns that suggest different functions for the two molecules. Following the selective death of photoreceptors in the adult, mdka and mdkb are co-expressed in horizontal cells and proliferating Müller glia and their neurogenic progeny. These data reveal that Mdka and Mdkb are signaling factors present in the retinal stem cell niches in both embryonic and mature retinas, and that their cellular expression is actively modulated during retinal development and regeneration. Experiment Overall Design: As a means to identify genes necessary for photoreceptor regeneration, we evaluated transcriptional in the retina of the zebrafish as photoreceptors are regenerated. Albino zebrafish were dark adapted, then half were exposed to bright constant light and half were returned to normal lighting. After 72hrs of light exposure, retinal RNA was isolated and analysis of gene expression was performed using Affymetriz zebrafish gene arrays.
2009-01-13 | E-GEOD-13999 | biostudies-arrayexpress
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: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:In the retina of adult teleosts, stem cells are sustained in two specialized niches: the ciliary marginal zone (CMZ) and the microenvironment surrounding adult Müller glia. Recently, Müller glia were identified as the regenerative stem cells in the teleost retina. Secreted signaling molecules that regulate neuronal regeneration in the retina are largely unknown. In a microarray screen to discover such factors, we identified midkine-b (mdkb). Midkine is a highly conserved heparin-binding growth factor with numerous biological functions. The zebrafish genome encodes two distinct midkine genes: mdka and mdkb. Here, we describe the cellular expression of mdka and mdkb during retinal development and the initial, proliferative phase of photoreceptor regeneration. The results show that in the embryonic and larval retina mdka and mdkb are expressed in stem cells, retinal progenitors and neurons in distinct patterns that suggest different functions for the two molecules. Following the selective death of photoreceptors in the adult, mdka and mdkb are co-expressed in horizontal cells and proliferating Müller glia and their neurogenic progeny. These data reveal that Mdka and Mdkb are signaling factors present in the retinal stem cell niches in both embryonic and mature retinas, and that their cellular expression is actively modulated during retinal development and regeneration.
2008-12-17 | GSE13999 | GEO
Project description:RNA Sequencing to Identify Regulators of Axon Regeneration in Mouse Retinal Ganglion Cells
| PRJNA475692 | ENA
Project description:The zebrafish (Danio rerio) is widely used to investigate the cellular and molecular mechanisms that support retinal regeneration. Although several adult injury paradigms have been established, models that capture the earliest stages of degeneration and Müller glia-mediated repair in larvae remain comparatively underexplored. Here, we validate a light-induced retinal degeneration (LIRD) paradigm at the larval stage as a tractable system to study acute phototoxic injury and early regenerative responses. This approach enables high-throughput RNA sequencing and provides a comprehensive transcriptomic view of retinal responses 48 hours after injury. At this timepoint, larvae display photoreceptor loss and robust Müller glia activation and proliferation, mirroring key features described in adult LIRD models. Transcriptomic analyses further highlight both canonical and previously undercharacterised pathways engaged during the early injury response. Together, this work establishes larval LIRD as a practical and informative model and provides a resource for hypothesis-driven studies aimed at dissecting the molecular events that initiate retinal regeneration.
2025-12-15 | GSE313277 | GEO
Project description:Following photoreceptors ablation by intense light exposure, adult zebrafish are capable of complete regeneration due to the ability of their Müller glia (MG) to re-enter the cell cycle, creating progenitors that differentiate into new photoreceptors. The majority of previous reports on retinal regeneration focused on the first few days of the regenerative response, which include MG cell-cycle re-entry and progenitor cell proliferation. With this study, we analyzed the full 28-day time-course of regeneration by pairing a detailed morphological/immunological analysis with RNA-seq transcriptional profiling at 8 key time points during retinal regeneration. We observed several novel findings. First, we provide evidence for two separate peaks of MG gliosis, with the secondary gliotic peak occurring after MG cell-cycle re-entry. Second, we highlight a distinct transcriptional shift between 5- and 10-days post lesion that highlights the transition from progenitor proliferation to differentiation into new photoreceptors. Third, we show distinctly different patterns of transcriptional recovery of the photoreceptor opsins at 28 days post lesion. Finally, using differential gene expression analysis, we revealed that the established functional recovery of the retina at 28 days post lesion does not, in fact, return to an undamaged transcriptional state, potentially redefining what the field considers complete regeneration. Together, to our knowledge, this work represents the first histological and transcriptomic map of a 28-day time-course of retinal regeneration in adult zebrafish.
2021-10-11 | GSE180518 | 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.
2014-09-20 | GSE58702 | GEO
Project description:Injury induces retinal Muller glia of non-mammalian, but not mammalian, vertebrates to generate neurons. To identify gene regulatory networks that control neurogenic competence in retinal glia, we used bulk and single-cell RNA-seq and ATAC-seq analysis to comprehensively profile gene expression and chromatin conformation in Muller glia from zebrafish, chick and mice. This was conducted during glial development, following inner and outer retinal injury, as well as following treatment with extrinsic factors that induce glial reprogramming. Integration of these data, together with functional analysis of candidate genes, identified evolutionarily conserved and species-specific gene regulatory networks controlling glial quiescence, gliosis, and neurogenic competence. In zebrafish and chick, transition from quiescence to gliosis is a necessary stage in acquisition of neurogenic competence, while in mice a dedicated network suppresses this transition and rapidly restores quiescence. These findings may help guide the design of cell-based therapies aimed at restoring retinal neurons lost to disease.
2020-05-01 | GSE135406 | GEO