Faculty Collaboration Database

Regeneration of the zebrafish retinal pigment epithelium after widespread genetic ablation. PLoS Genet 2019 Jan;15(1):e1007939

Date

01/30/2019

Pubmed ID

30695061

Pubmed Central ID

PMC6368336

DOI

10.1371/journal.pgen.1007939

Scopus ID

2-s2.0-85061272556 (requires institutional sign-in at Scopus site)   34 Citations

Abstract

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.

Author List

Hanovice NJ, Leach LL, Slater K, Gabriel AE, Romanovicz D, Shao E, Collery R, Burton EA, Lathrop KL, Link BA, Gross JM

Authors

Ross F. Collery PhD Assistant Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
Brian A. Link PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Animals, Genetically Modified
Apoptosis
Bruch Membrane
Cell Differentiation
Disease Models, Animal
Green Fluorescent Proteins
Humans
Imides
Larva
Macular Degeneration
Photoreceptor Cells
Quinolines
Regeneration
Retina
Retinal Pigment Epithelium
Wnt Signaling Pathway
Zebrafish
cis-trans-Isomerases