Abstract
Müller glia in the zebrafish retina respond to retinal damage by re-entering the cell cycle, which generates large numbers of retinal progenitors that ultimately replace the lost neurons. In this study we compared the regenerative outcomes of adult zebrafish exposed to one round of phototoxic treatment with adult zebrafish exposed to six consecutive rounds of phototoxic treatment. We observed that Müller glia continued to re-enter the cell cycle to produce clusters of retinal progenitors in zebrafish exposed to multiple rounds of phototoxic light. Some abnormalities were noted, however. First, we found that retinas exposed to multiple rounds of damage exhibited a greater loss of photoreceptors at 36 hours of light damage than retinas that were exposed to their first round of light damage. In addition, we found that Müller glia appeared to have an increase in the acute gliotic response in retinas exposed to multiple rounds of light treatment. This was evidenced by cellular hypertrophy, changes in GFAP cellular localization, and transient increases in stat3 and gfap expression. Finally, following the sixth round of phototoxic lesion, we observed a significant increase in mis-localized HuC/D-positive amacrine and ganglion cells in the inner plexiform layer and outer retina, and a decreased number of regenerated blue cone photoreceptors. These data add to recent findings that retinal regeneration in adult zebrafish occurs concomitant with Müller glia reactivity and can result in the generation of aberrant neurons. These data are also the first to demonstrate that Müller glia appear to modify their phenotype in response to multiple rounds of phototoxic lesion, exhibiting an increase in acute gliosis while maintaining a remarkable capacity for long-term regeneration of photoreceptors.
Highlights
Adult zebrafish (Danio rerio) have the ability to regenerate numerous different tissues including cardiac tissue, retinal tissue, and large portions of their appendages (Chablais et al, 2011; Gonzalez-Rosa et al, 2011; Poss, Wilson & Keating, 2002; Schnabel et al, 2011)
When we analyzed the regenerative potential of the retina following six rounds of phototoxic treatment, we found that Müller glia still re-entered the cell cycle to produce retinal progenitors
The resultant progenitors continue to proliferate over the 3 days as they migrate from the inner nuclear layer (INL) to the outer nuclear layer (ONL), where they begin to differentiate into new photoreceptors during the following week
Summary
Adult zebrafish (Danio rerio) have the ability to regenerate numerous different tissues including cardiac tissue, retinal tissue, and large portions of their appendages (i.e., fins) (Chablais et al, 2011; Gonzalez-Rosa et al, 2011; Poss, Wilson & Keating, 2002; Schnabel et al, 2011). These capabilities are contrasted in mammalian species by the formation of scars in these tissues rather than complete regeneration. The genes mps and hspd, which are necessary for proper regeneration in the heart and fin, are upregulated in the regenerating zebrafish retina, indicating that the details of regenerative mechanisms in each tissue might be different, there may be overlapping genetic networks at play in zebrafish tissues that allow them this unique regenerative quality (Qin, Barthel & Raymond, 2009)
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