Regeneration of inner retinal neurons after intravitreal injection of ouabain in zebrafish
Open accessAbstract
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.
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The zebrafish retina is a useful model for uncovering how stem cells activate and astrocytes dedifferentiate because it regenerates robustly after injury and this regeneration requires Müller glia dedifferentiation.
“The zebrafish retina is an important model for revealing these mechanisms since the retina is able to mount a robust regenerative response following injury and this response is dependent on the dedifferentiation of Müller glia (MG)”
From HB-EGF is Necessary and Sufficient for Müller Glia Dedifferentiation and Retina Regeneration (2012) · cites this paper as Fimbel et al., 2007
Müller glia mount a regenerative response regardless of whether injury affects only photoreceptors, inner retinal neurons, or all retinal cell types.
“It is interesting that MG elicit a regenerative response regardless if injury affects only photoreceptors, inner retinal neurons or all retinal cell types (Fausett and Goldman, 2006; Fimbel et al., 2007; Montgomery et al., 2010; Vihtelic and Hyde, 2000).”
From Retinal injury, growth factors, and cytokines converge on β-catenin and pStat3 signaling to stimulate retina regeneration (2014) · cites this paper as Fimbel et al., 2007
Müller glia are key to successful retina regeneration.
“Key to successful retina regeneration are Müller glia (MG), the major glial cell-type in the retina (Bernardos et al., 2007; Fausett and Goldman, 2006; Fimbel et al., 2007).”
From Retinal injury, growth factors, and cytokines converge on β-catenin and pStat3 signaling to stimulate retina regeneration (2014) · cites this paper as Fimbel et al., 2007
Müller glia mount a similar response to many different injuries, whether the injuries are restricted to specific cell types or more widespread.
“It is interesting that MG mount a similar response to a variety of injuries regardless if these injuries are restricted to specific cell types or more widespread (Fausett and Goldman, 2006; Fimbel et al., 2007; Montgomery et al., 2010; Vihtelic and Hyde, 2000).”
From Retinal injury, growth factors, and cytokines converge on β-catenin and pStat3 signaling to stimulate retina regeneration (2014) · cites this paper as Fimbel et al., 2007
A positive control with ouabain was included in the TUNEL assay.
“Eyes intravitreally injected of 3µM ouabain were included as a positive control (Fimbel et al., 2007).”
From Retinal injury, growth factors, and cytokines converge on β-catenin and pStat3 signaling to stimulate retina regeneration (2014) · cites this paper as Fimbel et al., 2007
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“It is interesting that MG mount a similar response to a variety of injuries regardless if these injuries are restricted to specific cell types or more widespread (Fausett and Goldman, 2006; Fimbel et al., 2007; Montgomery et al., 2010; Vihtelic and Hyde, 2000).”
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Self-citationFgf signaling is required for photoreceptor maintenance in the adult zebrafish retina
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- Authors
- Fimbel, S. M., Montgomery, J. E., Burket, C. T., & Hyde, D. R.
- Affiliations
- University of Notre Dame (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-02-14
- Volume
- 27
- Issue
- 7
- Pages
- 1712-1724
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6673754
- OpenAlex
- W2099636023
- Cited by
- 298
- References
- 52
- Citations by year
- 2026: 13 · 2025: 5 · 2024: 9 · 2023: 16 · 2022: 23 · 2021: 18 · 2020: 17 · 2019: 17 · 2018: 16 · 2017: 15 · 2016: 15 · 2015: 17 · 2014: 18 · 2013: 19 · 2012: 19
- FWCI
- 5.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Vanderbilt University
- University of Notre Dame
- Institute of Genetics
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Keywords
- retinal regeneration, ouabain, ganglion cell loss, amacrine cells, Müller cells, neural progenitor cells, Olig2, Atoh7, PCNA, zebrafish retina, inner nuclear layer, optic nerve diameter, cell cycle re-entry
- MeSH terms
- ELAV-Like Protein 3, Oligodendrocyte Transcription Factor 2, Analysis of Variance, Animals, Dose-Response Relationship, Drug, Enzyme Inhibitors, Glial Fibrillary Acidic Protein, Immunohistochemistry, Nerve Tissue Proteins, Neuroglia, Ouabain, Regeneration, Retina, Retinal Ganglion Cells, Time Factors, Zebrafish, Blotting, Western, Proliferating Cell Nuclear Antigen, In Situ Nick-End Labeling, Zebrafish Proteins, Animals, Genetically Modified, Green Fluorescent Proteins, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, ELAV Proteins
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