Cited by 206Retinal Development and DisordersNeurogenesis and neuroplasticity mechanismsWnt/β-catenin signaling in development and cancer

Ascl1a/Dkk/β-catenin signaling pathway is necessary and glycogen synthase kinase-3β inhibition is sufficient for zebrafish retina regeneration

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Ramachandran, Rajesh, Zhao, Xiao-Feng, Goldman, Daniel·2011·Proceedings of the National Academy of Sciences

Abstract

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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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
Published
2011-09-12
Volume
108
Issue
38
Pages
15858-15863
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
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
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
  • 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 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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