Abstract
Purpose :
In contrast to mammals, zebrafish posses the remarkable ability to regenerate retinal neurons. Damage to the zebrafish retina induces Muller glia to act as stem cells, generating retinal progenitors for regeneration. In contrast, injury in the mammalian retina results in Muller glial reactive gliosis, a characteristic gliotic response that is detrimental to vision. The purpose of this study was threefold. First, we aimed to determine whether zebrafish Muller glia show any signs of reactive gliosis following retinal damage. Next, we tested whether multiple rounds of damage and regeneration resulted in increased gliosis or decreased regeneration. Finally, we tested whether inhibiting Muller glial cell cycle reentry resulted in an increased gliotic response.
Methods :
Adult albino zebrafish were exposed to constant intense light to damage photoreceptors. We analyzed the gliosis and regeneration response at multiple timepoints following light onset. In a separate study, we analyzed retinas that underwent six consecutive rounds of damage/regeneration. Finally, we analyzed retinas in which Muller glial proliferation was inhibited by intraocular injections of 5-Fluorouracil.
Results :
We provide evidence that Muller glia exhibited signs of reactive gliosis immediately following retinal damage, but then downregulated that response as large numbers of progenitors were generated. Next, we show that even after multiple rounds of damage and regeneration, retinas exhibited accelerated photoreceptor degeneration and some signs of increased reactive gliosis. However, photoreceptors were regenerated in normal numbers. Finally, cell cycle inhibition resulted in persistently gliotic Muller glia, which resulted in temporary neuroprotection of the photoreceptors to the cytotoxic lesion, but a significant long-term inhibition of retinal regeneration.
Conclusions :
Together, these data demonstrate that zebrafish Müller glia possess both gliotic and regenerative potential. Understanding the signaling pathways that determine how Müller glia respond to injury is a critical step toward promoting regeneration in the mammalian retina.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.