Abstract
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.
Highlights
According to the CDC, there are currently over 12 million Americans suffering from vision loss due to diseases affecting the retina, including diabetic retinopathy, glaucoma, and age-related macular degeneration (Wittenborn et al, 2013)
To determine whether distinct differences were apparent in the transcriptomes of the retinas for each time point, we performed a principal component analysis (PCA) using the top 200 differentially regulated genes, all which had an FDR < 0.05
We provide an updated expression map of the complete 28day cycle of retinal degeneration and regeneration in adult zebrafish
Summary
According to the CDC, there are currently over 12 million Americans suffering from vision loss due to diseases affecting the retina, including diabetic retinopathy, glaucoma, and age-related macular degeneration (Wittenborn et al, 2013). Following retinal damage in mammals, Müller glia (MG) of the retina undergo an acute gliosis, activating various cytoskeletal and neuroprotective gene pathways and releasing neurotrophic factors and free radical scavengers (Bringmann et al, 2009; Hippert et al, 2015). This initial damage response is neuroprotective to retinal neurons. In response to phototoxic degeneration of rod and cone photoreceptors, zebrafish MG undergo an asymmetric cell division, generating one Müller glia-derived progenitor cell (MGPC) and one MG that retains its innate glial function (Nagashima et al, 2013). Functional recovery of vision occurs by 28 days post lesion, a time point largely used by the field as complete regeneration (Ramachandran et al, 2011; Wan et al, 2012; Nelson et al, 2013; Taylor et al, 2015; Wan and Goldman, 2017)
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