Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 38, Pages 15858-15863Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1107220108
Keywords
pyrvinium; XAV939; transgenic zebrafish; heat shock; frizzled
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Funding
- National Institutes of Health [NEI R01 EY018132]
- National Institutes of Health National Institute of Child Health and Human Development [T32HD007507]
- University of Michigan Center for Organogenesis
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Key to successful retina regeneration in zebrafish are Muller 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-3 beta (GSK-3 beta) 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-3 beta inhibition, in particular, are crucial for successful retina regeneration.
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