title: β-catenin/Wnt signaling controls progenitor fate in the developing and regenerating zebrafish retina.
abstract: 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.
authors.affiliation: Department of Biology, Colgate University, Hamilton, NY 13346, USA. jmeyers@colgate.edu
authors.forename: Jason R
authors.initials: JR
authors.lastname: Meyers
authors.forename: Lily
authors.initials: L
authors.lastname: Hu
authors.forename: Ariel
authors.initials: A
authors.lastname: Moses
authors.forename: Kavon
authors.initials: K
authors.lastname: Kaboli
authors.forename: Annemarie
authors.initials: A
authors.lastname: Papandrea
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Raymond
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001552:Benzazepines / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005136:Eye Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007814:Larva; D009154:Mutation / Q000235:genetics; D009416:Nerve Regeneration / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D012160:Retina / Q000166:cytology* / Q000254:growth & development* / Q000293:injuries / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells; D055747:SOX Transcription Factors / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D001552:Benzazepines; D004791:Enzyme Inhibitors; D005136:Eye Proteins; D006575:Heterocyclic Compounds, 3-Ring; D018398:Homeodomain Proteins; D007211:Indoles; D055747:SOX Transcription Factors; C544611:Sox2 protein, zebrafish; C544261:XAV939; D029961:Zebrafish Proteins; D051176:beta Catenin; C119620:kenpaullone; C464524:rx1 protein, zebrafish; C108000:vsx2 protein, zebrafish; D049452:Green Fluorescent Proteins