Dataset Information

Muller Glia maintain their regenerative potential despite degeneration in the aged zebrafish retina.

ABSTRACT: Ageing is a significant risk factor for degeneration of the retina. Müller glia cells (MG) are key for neuronal regeneration, so harnessing the regenerative capacity of MG in the retina offers great promise for the treatment of age-associated blinding conditions. Yet, the impact of ageing on MG regenerative capacity is unclear. Here, we show that the zebrafish retina undergoes telomerase-independent, age-related neurodegeneration but that this is insufficient to stimulate MG proliferation and regeneration. Instead, age-related neurodegeneration is accompanied by MG morphological aberrations and loss of vision. Mechanistically, yes-associated protein (Yap), part of the Hippo signalling, has been shown to be critical for the regenerative response in the damaged retina, and we show that Yap expression levels decline with ageing. Despite this, morphologically and molecularly altered aged MG retain the capacity to regenerate neurons after acute light damage, therefore, highlighting key differences in the MG response to high-intensity acute damage versus chronic neuronal loss in the zebrafish retina.

SUBMITTER: Martins RR

PROVIDER: S-EPMC9009236 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Müller Glia maintain their regenerative potential despite degeneration in the aged zebrafish retina.

Martins Raquel R RR Zamzam Mazen M Tracey-White Dhani D Moosajee Mariya M Thummel Ryan R Henriques Catarina M CM MacDonald Ryan B RB

Aging cell 20220322 4

Ageing is a significant risk factor for degeneration of the retina. Müller glia cells (MG) are key for neuronal regeneration, so harnessing the regenerative capacity of MG in the retina offers great promise for the treatment of age-associated blinding conditions. Yet, the impact of ageing on MG regenerative capacity is unclear. Here, we show that the zebrafish retina undergoes telomerase-independent, age-related neurodegeneration but that this is insufficient to stimulate MG proliferation and re ...[more]

PMID: 35315590

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Project description:IntroductionLoss of neurons in the neural retina is a leading cause of vision loss. While humans do not possess the capacity for retinal regeneration, zebrafish can achieve this through activation of resident Müller glia. Remarkably, despite the presence of Müller glia in humans and other mammalian vertebrates, these cells lack an intrinsic ability to contribute to regeneration. Upon activation, zebrafish Müller glia can adopt a stem cell-like state, undergo proliferation and generate new neurons. However, the underlying molecular mechanisms of this activation subsequent retinal regeneration remains unclear.Methods/resultsTo address this, we performed single-cell RNA sequencing (scRNA-seq) and report remarkable heterogeneity in gene expression within quiescent Müller glia across distinct dorsal, central and ventral retina pools of such cells. Next, we utilized a genetically driven, chemically inducible nitroreductase approach to study Müller glia activation following selective ablation of three distinct photoreceptor subtypes: long wavelength sensitive cones, short wavelength sensitive cones, and rods. There, our data revealed that a region-specific bias in activation of Müller glia exists in the zebrafish retina, and this is independent of the distribution of the ablated cell type across retinal regions. Notably, gene ontology analysis revealed that injury-responsive dorsal and central Müller glia express genes related to dorsal/ventral pattern formation, growth factor activity, and regulation of developmental process. Through scRNA-seq analysis, we identify a shared genetic program underlying initial Müller glia activation and cell cycle entry, followed by differences that drive the fate of regenerating neurons. We observed an initial expression of AP-1 and injury-responsive transcription factors, followed by genes involved in Notch signaling, ribosome biogenesis and gliogenesis, and finally expression of cell cycle, chromatin remodeling and microtubule-associated genes.DiscussionTaken together, our findings document the regional specificity of gene expression within quiescent Müller glia and demonstrate unique Müller glia activation and regeneration features following neural ablation. These findings will improve our understanding of the molecular pathways relevant to neural regeneration in the retina.

Project description:Upon retinal injury, zebrafish Müller glia (MG) transition from a quiescent supportive cell to a progenitor cell (MGPC). This event is accompanied by the induction of key transcription and pluripotency factors. Because somatic cell reprogramming during iPSC generation is accompanied by changes in DNA methylation, especially in pluripotency factor gene promoters, we were interested in determining if DNA methylation changes also underlie MG reprogramming following retinal injury. Consistent with this idea, we found that genes encoding components of the DNA methylation/demethylation machinery were induced in MGPCs and that manipulating MGPC DNA methylation with 5-aza-2’-deoxycytidine altered their properties. A comprehensive analysis of the DNA methylation landscape as MG reprogram to MGPCs revealed that demethylation predominates at early times, while levels of de novo methylation increase at later times. We found that these changes in DNA methylation were largely independent of Apobec2 protein expression. A correlation between promoter DNA demethylation and injury-dependent gene induction was noted. In contrast to iPSC formation, we found that pluripotency factor gene promoters were already hypomethylated in quiescent MG and remained unchanged in MGPCs. Interestingly, these pluripotency factor promoters were also found to be hypomethylated in mouse MG. Our data identify a dynamic DNA methylation landscape as zebrafish MG transition to a MGPC and suggest that DNA methylation changes will complement other regulatory mechanisms to ensure gene expression programs controlling MG reprogramming are appropriately activated during retina regeneration. Reduced representation bisulfite sequencing (MspI,~40-220bp size fraction) of zebrafish MG before and after injury. This dataset includes 4 replicated samples: The MG samples report the genomic methylation of a quiescent state. The 4dpi MGPC sampes report the methylation of a dedifferentiated, proliferating progenitor. The 2dpi morpholino samples report the genomic methylation of a dedifferentiated MGPC following a conrtol or Apobec2a,2b knockdown.

Dataset Information

Muller Glia maintain their regenerative potential despite degeneration in the aged zebrafish retina.

Publications

Müller Glia maintain their regenerative potential despite degeneration in the aged zebrafish retina.

Similar Datasets

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