β-catenin/Wnt signaling controls progenitor fate in the developing and regenerating zebrafish retina
Open accessAbstract
Background: The zebrafish retina maintains two populations of stem cells: first, the germinal zone or ciliary marginal zone (CMZ) contains multipotent retinal progenitors that add cells to the retinal periphery as the fish continue to grow; second, radial glia (Müller cells) occasionally divide asymmetrically to generate committed progenitors that differentiate into rod photoreceptors, which are added interstitially throughout the retina with growth. Retinal injury stimulates Müller glia to dedifferentiate, re-enter the cell cycle, and generate multipotent retinal progenitors similar to those in the CMZ to replace missing neurons. The specific signals that maintain these two distinct populations of endogenous retinal stem cells are not understood. Results: We used genetic and pharmacological manipulation of the β-catenin/Wnt signaling pathway to show that it is required to maintain proliferation in the CMZ and that hyperstimulation of β-catenin/Wnt signaling inhibits normal retinal differentiation and expands the population of proliferative retinal progenitors. To test whether similar effects occur during regeneration, we developed a method for making rapid, selective photoreceptor ablations in larval zebrafish with intense light. We found that dephosphorylated β-catenin accumulates in Müller glia as they re-enter the cell cycle following injury, but not in Müller glia that remain quiescent. Activation of Wnt signaling is required for regenerative proliferation, and hyperstimulation results in loss of Müller glia from the INL as all proliferative cells move into the ONL. Conclusions: β-catenin/Wnt signaling is thus required for the maintenance of retinal progenitors during both initial development and lesion-induced regeneration, and is sufficient to prevent differentiation of those progenitors and maintain them in a proliferative state. This suggests that the β-catenin/Wnt cascade is part of the shared molecular circuitry that maintains retinal stem cells for both homeostatic growth and epimorphic regeneration.
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Wnt/Gsk3β/β-catenin signaling has been implicated in regulating injury-dependent Müller glia proliferation.
“Wnt/Gsk3β/β-catenin has been implicated in regulating injury-dependent MG proliferation (Meyers et al., 2012; Ramachandran et al., 2011).”
From Retinal injury, growth factors, and cytokines converge on β-catenin and pStat3 signaling to stimulate retina regeneration (2014) · cites this paper as Meyers et al., 2012
Previous studies indicate that Mapk/Erk, Gsk3β/β-catenin and Jak/Stat3 signaling regulate Müller glia-dependent progenitor formation in the injured retina.
“Previous studies (Kassen et al., 2009; Meyers et al., 2012; Nelson et al., 2012; Ramachandran et al., 2011; Wan, 2012), along with the accompanying paper by Zhao et al., indicate that Mapk/Erk, Gsk3 β/β-catenin and Jak/Stat3 signaling regulate MG-dependent progenitor formation in the injured retina.”
From Retinal injury, growth factors, and cytokines converge on β-catenin and pStat3 signaling to stimulate retina regeneration (2014) · cites this paper as Meyers et al., 2012
In the injured retina, β-catenin and pStat3 are restricted to Müller glia-derived progenitors.
“In the injured retina, β-catenin (Meyers et al., 2012; Ramachandran et al., 2011) and pStat3 (see accompanying paper by Zhao et al.) are restricted to MG-derived progenitors.”
From Retinal injury, growth factors, and cytokines converge on β-catenin and pStat3 signaling to stimulate retina regeneration (2014) · cites this paper as Meyers et al., 2012
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Wan, J., Zhao, X.-F., Vojtek, A., & Goldman, D. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.048 · Cited by 143 · see citing works
“…a regulatory role for Mapk/Erk in controlling MG reprogramming in response to retinal injury or HB-EGF-treatment of the uninjured retina (Wan, 2012) and Wnt/Gsk3β/β-catenin has been implicated in regulating injury-dependent MG proliferation (Meyers et al., 2012; Ramachandran et al., 2011).”
Background
- Authors
- Meyers, J. R., Hu, L., Moses, A., Kaboli, K., Papandrea, A., & Raymond, P. A.
- Affiliations
- Colgate University (US)
- University of Michigan (US)
- Corresponding author
- Meyers, Jason R
- Venue
- Neural Development
- Published
- 2012-08-24
- Volume
- 7
- Issue
- 1
- Pages
- 30-30
- ISSN
- 1749-8104 (ISSN-L)
- PMC
- PMC3549768
- OpenAlex
- W2159234350
- Cited by
- 144
- References
- 49
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 6 · 2023: 10 · 2022: 11 · 2021: 12 · 2020: 13 · 2019: 11 · 2018: 12 · 2017: 9 · 2016: 7 · 2015: 14 · 2014: 13 · 2013: 13
- FWCI
- 5.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Neural Development (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (0923310)
- National Institutes of Health (NIH-R01)
- National Eye Institute (R01EY004318, F32EY017251)
- Division of Biological Infrastructure
- 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 › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- retinal progenitor cells, retinal stem cells, ciliary marginal zone, Müller cells, retinal regeneration, retinal development, progenitor cell proliferation, progenitor cell differentiation, zebrafish retina
- MeSH terms
- Animals, Benzazepines, Cell Cycle, Cell Differentiation, Dose-Response Relationship, Drug, Embryo, Nonmammalian, Enzyme Inhibitors, Eye Proteins, Heterocyclic Compounds, 3-Ring, Indoles, Larva, Mutation, Nerve Regeneration, Neuroglia, Retina, Stem Cells, Time Factors, Zebrafish, Retinal Rod Photoreceptor Cells, Homeodomain Proteins, Gene Expression Regulation, Developmental, Zebrafish Proteins, Animals, Genetically Modified, Cell Proliferation, Green Fluorescent Proteins, beta Catenin, Neurogenesis, SOX Transcription Factors, Wnt Signaling Pathway
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