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Ascl1a/Dkk/β-catenin signaling pathway is necessary and glycogen synthase kinase-3β inhibition is sufficient for zebrafish retina regeneration
Open accessAbstract
Key to successful retina regeneration in zebrafish are Müller glia (MG) that respond to retinal injury by dedifferentiating into a cycling population of retinal progenitors. Although recent studies have identified several genes involved in retina regeneration, the signaling mechanisms underlying injury-dependent MG proliferation have remained elusive. Here we report that canonical Wnt signaling controls the proliferation of MG-derived retinal progenitors. We found that injury-dependent induction of Ascl1a suppressed expression of the Wnt signaling inhibitor, Dkk, and induced expression of the Wnt ligand, Wnt4a. Genetic and pharmacological inhibition of Wnt signaling suppressed injury-dependent proliferation of MG-derived progenitors. Remarkably, in the uninjured retina, glycogen synthase kinase-3β (GSK-3β) inhibition was sufficient to stimulate MG dedifferentiation and the formation of multipotent retinal progenitors that were capable of differentiating into all major retinal cell types. Importantly, Ascl1a expression was found to contribute to the multipotential character of these progenitors. Our data suggest that Wnt signaling and GSK-3β inhibition, in particular, are crucial for successful retina regeneration.
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“Previous studies showed Ascl1a controls c-mycb expression, and that Ascl1a and Pax6b act in parallel but independent pathways”
From HB-EGF is Necessary and Sufficient for Müller Glia Dedifferentiation and Retina Regeneration (2012) · cites this paper as Ramachandran et al., 2011
In the citing paper
“We recently found that activation of a canonical Wnt/β-catenin signaling cascade is necessary for the generation of a proliferating population of retinal progenitors in the injured retina (Ramachandran et al., 2011).”
From HB-EGF is Necessary and Sufficient for Müller Glia Dedifferentiation and Retina Regeneration (2012) · cites this paper as Ramachandran et al., 2011
In the citing paper
“HB-EGF also activated the Wnt/β-catenin signaling cascade which we recently showed was necessary for MG proliferation (Ramachandran et al., 2011).”
From HB-EGF is Necessary and Sufficient for Müller Glia Dedifferentiation and Retina Regeneration (2012) · cites this paper as Ramachandran et al., 2011
In the citing paper
“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 Ramachandran et al., 2011
In the citing paper
“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 Ramachandran et al., 2011
In the citing paper
“We note that although wnt4a mRNA has been reported to be induced by retinal injury (Ramachandran et al., 2011), we could not detect its induction by the growth factors or cytokines tested here (data not shown).”
From Retinal injury, growth factors, and cytokines converge on β-catenin and pStat3 signaling to stimulate retina regeneration (2014) · cites this paper as Ramachandran et al., 2011
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Metadata
- Authors
- Ramachandran, R., Zhao, X.-F., & Goldman, D.
- Affiliations
- University of Michigan (US)
- Molecular and Behavioral Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-09-12
- Volume
- 108
- Issue
- 38
- Pages
- 15858-15863
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3179085
- OpenAlex
- W2021643095
- Cited by
- 206
- References
- 37
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 9 · 2023: 20 · 2022: 18 · 2021: 11 · 2020: 14 · 2019: 21 · 2018: 10 · 2017: 12 · 2016: 12 · 2015: 18 · 2014: 25 · 2013: 11 · 2012: 11
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Michigan
- National Institutes of Health
- National Eye Institute (R01EY018132)
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007507)
- Topics
- Health Sciences › Medicine › Ophthalmology › 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 regeneration, Müller cells, Wnt signaling, β-catenin, glycogen synthase kinase-3β inhibition, retinal progenitor cells, retinal damage, zebrafish
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Enzyme Inhibitors, Microscopy, Fluorescence, Neuroglia, Regeneration, Retina, Stem Cells, Transcription Factors, Zebrafish, Signal Transduction, In Situ Hybridization, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Zebrafish Proteins, Animals, Genetically Modified, Intercellular Signaling Peptides and Proteins, Glycogen Synthase Kinase 3, Cell Proliferation, Green Fluorescent Proteins, beta Catenin, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Cell Dedifferentiation, Gene Knockdown Techniques, Wnt4 Protein
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