Abstract
Purpose The loss of Dicer in Müller glia (MG) results in severe photoreceptor degeneration as it occurs in retinitis pigmentosa or AMD. However, the sequence of events leading to this severe degenerative state is unknown. The aim of this study was to conduct a chronological functional and structural characterization of the pathological events in MG-specific Dicer-cKO mice in vivo and histologically.
Methods To delete Dicer and mature microRNAs (miRNAs) in MG, two conditional Dicer1 knock-out mouse strains namely RlbpCre:Dicer-cKOMG and GlastCre:Dicer-cKOMG, were created. Optical coherence tomography (OCT), electroretinograms (ERGs) as well as histological analyses were conducted to investigate structural and functional changes up to six months after Dicer deletion.
Results Dicer/miRNA loss in MG leads to 1) impairments of the external limiting membrane (ELM) – retinal pigment epithelium (RPE), 2) cone photoreceptor dysfunction and 3) retinal remodeling and functional loss of the inner retina, 1, 3 and 6 months after Dicer loss, respectively, in both strains. Furthermore, in the Rlbp:Dicer-cKOMG strain, rod photoreceptor impairment was found 4 months after Dicer depletion (4) accompanied by alteration of RPE integrity (5).
Conclusions MG Dicer loss in the adult mouse retina impacts cone function prior to any measurable changes in rod function, suggesting a pivotal role for MG Dicer and miRNAs in supporting cone health. A partially impaired RPE however seems to accelerate rod degeneration and overall degenerative events.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Funding: This study was funded by the New York Empire Innovation Program Grant to S.G.W, the National Eye Institute (NEI, R01 EY032532) to S.G.W., SUNY Startup Funds to S.G.W, SUNY Graduate Assistantship to D.L., S.K. and S.C., NEI T35 to A.M.R, NEI R01 EY024373 and R21 EY032724 to S.F. Catalyst Award from Research to Prevent Blindness Inc./American Macular Degeneration Foundation to S.F., an unrestricted award to the Department of Ophthalmology and Visual Sciences from Research to Prevent Blindness, Inc.
Commercial Relationships Disclosure: none
