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Beyond canonical pathways: early retinal transcriptomic response to light-induced degeneration in the zebrafish larva

ABSTRACT: 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.

ORGANISM(S): Danio rerio

PROVIDER: GSE313277 | GEO | 2025/12/15

REPOSITORIES: GEO

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Project description:Loss of neurons in the neural retina is a leading cause of vision loss. Retinal regeneration in zebrafish is attributed to Müller glia, which are activated, adopt a stem cell-like state, proliferate, and generate new neurons. Despite the same endogenous Müller glia being present in all vertebrates including humans, Müller glia activation in mammals leads to glial scarring instead of neurogenesis. Therefore, understanding Müller glia cellular states and molecular processes during zebrafish regeneration may allow us to improve mammalian regeneration. Since only a subset of Müller glia activate following neuron loss, we asked whether a specialised subset of Müller glia might be genetically primed for activation. Single-cell RNA sequencing (sc-RNAseq) from integrated zebrafish Müller glia samples reveals heterogeneity of gene expression across the quiescent Müller glia pool with 4 main clusters emerging, two of which are genetically similar. Labelling for key differentially expressed markers identified that these main clusters correlated with glia spatially distributed across dorsal, central and ventral retina. Using a genetically driven, chemically induced nitroreductase approach, three distinct photoreceptor types were ablated: the long (Lws2), short wavelength-sensitive (Sws2) and rod (Xops) photoreceptors, which also differ in their abundance. As expected, histological analysis of the three injuries and sc-RNAseq data for the two cone photoreceptor ablations identified common genetic program involved in the transition of Müller glia quiescence to activation, and differential responses to injury related to either injury extent or subtype of photoreceptor targeted. Interestingly, despite differences in the distributed across the retina, biased activation of Müller glia was observed in dorsal and central regions. Gene ontology analysis revealed that these injury-responsive dorsal and central Müller glia express genes related to dorsal/ventral pattern formation, growth factor activity, and regulation of developmental process. Müller glia upregulated genes related to homeostasis as well as certain AP-1 and injury-responsive transcription factors, followed by expression of genes involved in cell cycle, chromatin remodeling, and microtubule organisation. Prior to cell cycle entry, Müller glia show a transient upregulation of genes involved in gliogenesis, and Notch signalling. These findings enhance our understanding of heterogeneous states of quiescent Müller glia, and how these differences relate to activation and regeneration potential following neural ablation. A comparison of the distinct quiescent Müller glia with glia states in mammals will reveal key molecular pathways that could be targeted for improved mammalian neural regeneration.

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Beyond canonical pathways: early retinal transcriptomic response to light-induced degeneration in the zebrafish larva

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