Regeneration of the zebrafish retinal pigment epithelium after widespread genetic ablation

Hanovice, N.J., Leach, L.L., Slater, K., Gabriel, A.E., Romanovicz, D., Shao, E., Collery, R., Burton, E.A., Lathrop, K.L., Link, B.A., Gross, J.M.
PLoS Genetics   15: e1007939 (Journal)
Registered Authors
Burton, Edward A., Collery, Ross, Gross, Jeffrey, Hanovice, Nick, Leach, Lyndsay, Link, Brian
MeSH Terms
  • Animals
  • Animals, Genetically Modified/genetics
  • Animals, Genetically Modified/growth & development
  • Apoptosis/genetics
  • Bruch Membrane/growth & development
  • Bruch Membrane/metabolism
  • Cell Differentiation/genetics
  • Disease Models, Animal
  • Green Fluorescent Proteins/genetics
  • Humans
  • Imides/administration & dosage
  • Larva/genetics
  • Larva/growth & development
  • Macular Degeneration/genetics*
  • Macular Degeneration/pathology
  • Photoreceptor Cells/metabolism
  • Photoreceptor Cells/pathology
  • Quinolines/administration & dosage
  • Regeneration/genetics*
  • Retina/growth & development
  • Retina/pathology
  • Retinal Pigment Epithelium/growth & development*
  • Retinal Pigment Epithelium/metabolism
  • Wnt Signaling Pathway/drug effects
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • cis-trans-Isomerases/genetics*
30695061 Full text @ PLoS Genet.
The retinal pigment epithelium (RPE) is a specialized monolayer of pigmented cells within the eye that is critical for maintaining visual system function. Diseases affecting the RPE have dire consequences for vision, and the most prevalent of these is atrophic (dry) age-related macular degeneration (AMD), which is thought to result from RPE dysfunction and degeneration. An intriguing possibility for treating RPE degenerative diseases like atrophic AMD is the stimulation of endogenous RPE regeneration; however, very little is known about the mechanisms driving successful RPE regeneration in vivo. Here, we developed a zebrafish transgenic model (rpe65a:nfsB-eGFP) that enabled ablation of large swathes of mature RPE. RPE ablation resulted in rapid RPE degeneration, as well as degeneration of Bruch's membrane and underlying photoreceptors. Using this model, we demonstrate for the first time that zebrafish are capable of regenerating a functional RPE monolayer after RPE ablation. Regenerated RPE cells first appear at the periphery of the RPE, and regeneration proceeds in a peripheral-to-central fashion. RPE ablation elicits a robust proliferative response in the remaining RPE. Subsequently, proliferative cells move into the injury site and differentiate into RPE. BrdU incorporation assays demonstrate that the regenerated RPE is likely derived from remaining peripheral RPE cells. Pharmacological disruption using IWR-1, a Wnt signaling antagonist, significantly reduces cell proliferation in the RPE and impairs overall RPE recovery. These data demonstrate that the zebrafish RPE possesses a robust capacity for regeneration and highlight a potential mechanism through which endogenous RPE regenerate in vivo.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes