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The Journal of Neuroscience, February 14, 2007, 27(7):1712-1724; doi:10.1523/JNEUROSCI.5317-06.2007

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Development/Plasticity/Repair
Regeneration of Inner Retinal Neurons after Intravitreal Injection of Ouabain in Zebrafish

Shane M. Fimbel, Jacob E. Montgomery, Christopher T. Burket, and David R. Hyde

Department of Biological Sciences and Center for Zebrafish Research, University of Notre Dame, Notre Dame, Indiana 46556

Correspondence should be addressed to David R. Hyde, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556. Email: dhyde{at}nd.edu

We examined the regenerative capacity of the adult zebrafish retina by intravitreal injection of a low ouabain concentration to rapidly damage the ganglion cell layer (GCL) and inner nuclear layer (INL) with minimal photoreceptor cell damage. By 24 h after ouabain injection, maximal numbers of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL)-positive cells were detected in the INL and GCL, with low numbers of TUNEL-positive cells in the outer nuclear layer. Immunolabeling revealed that 85% of the HuC/D-positive amacrine and ganglion cells were lost by 7 d post-ouabain injection (dpi). This ganglion cell loss was consistent with the small, but statistically significant, decrease in the optic nerve diameter. The regeneration response began within 1 dpi with increased proliferating cell nuclear antigen (PCNA) expression in both the INL and GCL. By 3 dpi, PCNA expression is primarily restricted to the Müller glia. By 5 dpi, most of the PCNA expression was localized to neuronal progenitors expressing the olig2:egfp transgene rather than the Müller glia. By 7 dpi, the neuronal progenitors began committing to the ganglion cell fate based on the coexpression of the atoh7:EGFP transgene and the zn5 antigen. The regeneration of ganglion and amacrine cells continued until 60 dpi, when they reached 75% of their uninjected control number. This demonstrates that inner retinal damage, without extensive photoreceptor damage, is sufficient to induce a regeneration response that is marked by the Müller glial cells reentering the cell cycle to produce neuronal progenitor cells that regenerate INL and ganglion cells in the zebrafish retina.

Key words: retinal degeneration; retinal regeneration; retinal apoptosis; retinal progenitor; Müller glia; zebrafish

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Received July 27, 2006; revised Jan. 9, 2007; accepted Jan. 11, 2007.

Correspondence should be addressed to David R. Hyde, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556. Email: dhyde{at}nd.edu

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