Iron contributes to photoreceptor degeneration and Müller glia proliferation in the zebrafish light-treated retina

Boyd, Patrick; Hyde, David R.

doi:10.1016/j.exer.2022.108947

Cited by 6 publications

(2 citation statements)

References 74 publications

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“…However, this cellular engulfment, whilst correlated, did not seem sufficient to cause Müller glia activation. Müller glia are able to sense injury cues released by dying neurons, with detection of iron, ADP and TNFalpha implicated in Müller glia proliferation (Nelson et al, 2013; Conner et al, 2014; Medrano et al, 2017; Iribarne et al, 2019; Boyd and Hyde, 2022). Therefore, whether the intrinsic molecular state of Müller glia can influence their receptiveness to these “pro-regenerative”signals presents an area of future research.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity in quiescent Müller glia in the uninjured zebrafish retina drive differential responses following photoreceptor ablation

Krylov

Newton

et al. 2023

Preprint

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Loss 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. To 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 utilised 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 signalling, ribosome biogenesis and gliogenesis, and finally expression of cell cycle, chromatin remodeling and microtubule-associated genes. Taken 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.

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Section: Discussionmentioning

confidence: 99%

Heterogeneity in quiescent Müller glia in the uninjured zebrafish retina drive differential responses following photoreceptor ablation

Krylov

Newton

et al. 2023

Preprint

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show abstract

“…However, this cellular engulfment, while correlated, did not seem sufficient to cause Müller glia activation. Müller glia are able to sense injury cues released by dying neurons, with detection of iron, ADP and TNFalpha implicated in Müller glia proliferation ( Nelson et al, 2013 ; Conner et al, 2014 ; Medrano et al, 2017 ; Iribarne et al, 2019 ; Boyd and Hyde, 2022 ). Therefore, whether the intrinsic molecular state of Müller glia can influence their receptiveness to these “pro-regenerative” signals presents an area of future research.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity in quiescent Müller glia in the uninjured zebrafish retina drive differential responses following photoreceptor ablation

Krylov

Veen

et al. 2023

Front. Mol. Neurosci.

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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.

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Regulating the formation of Müller glia‐derived progenitor cells in the retina

Taylor,

El‐Hodiri,

Palazzo

et al. 2024

Glia

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We summarize recent findings in different animal models regarding the different cell‐signaling pathways and gene networks that influence the reprogramming of Müller glia into proliferating, neurogenic progenitor cells in the retina. Not surprisingly, most of the cell‐signaling pathways that guide the proliferation and differentiation of embryonic retinal progenitors also influence the ability of Müller glia to become proliferating Müller glia‐derived progenitor cells (MGPCs). Further, the neuronal differentiation of MGPC progeny is potently inhibited by networks of neurogenesis‐suppressing genes in chick and mouse models but occurs freely in zebrafish. There are important differences between the model systems, particularly pro‐inflammatory signals that are active in mature Müller glia in damaged rodent and chick retinas, but less so in fish retinas. These pro‐inflammatory signals are required to initiate the process of reprogramming, but if sustained suppress the potential of Müller glia to become neurogenic MGPCs. Further, there are important differences in how activated Müller glia up‐ or downregulate pro‐glial transcription factors in the different model systems. We review recent findings regarding regulatory cell signaling and gene networks that influence the activation of Müller glia and the transition of these glia into proliferating progenitor cells with neurogenic potential in fish, chick, and mouse model systems.

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Iron contributes to photoreceptor degeneration and Müller glia proliferation in the zebrafish light-treated retina

Cited by 6 publications

References 74 publications

Heterogeneity in quiescent Müller glia in the uninjured zebrafish retina drive differential responses following photoreceptor ablation

Heterogeneity in quiescent Müller glia in the uninjured zebrafish retina drive differential responses following photoreceptor ablation

Heterogeneity in quiescent Müller glia in the uninjured zebrafish retina drive differential responses following photoreceptor ablation

Regulating the formation of Müller glia‐derived progenitor cells in the retina

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