Next Article in Journal
Functional Phenotypes of Human Vγ9Vδ2 T Cells in Lymphoid Stress Surveillance
Next Article in Special Issue
The Interplay between Peripherin 2 Complex Formation and Degenerative Retinal Diseases
Previous Article in Journal
Validation of Reference Genes for Gene Expression Studies by RT-qPCR in HepaRG Cells during Toxicity Testing and Disease Modelling
Previous Article in Special Issue
From Rust to Quantum Biology: The Role of Iron in Retina Physiopathology
Open AccessArticle

Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration

1
Department of Optometry and Vision Science, Vision Science Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
2
Departments of Ophthalmology and Biochemistry, State University of New York-University at Buffalo, Buffalo, NY 14209, USA; and Research Service, VA Western NY Healthcare System, Buffalo, NY 14215, USA
*
Author to whom correspondence should be addressed.
Cells 2020, 9(3), 771; https://doi.org/10.3390/cells9030771
Received: 12 February 2020 / Revised: 6 March 2020 / Accepted: 17 March 2020 / Published: 21 March 2020
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
Patients with certain defects in the dehydrodolichyl diphosphate synthase (DHDDS) gene (RP59; OMIM #613861) exhibit classic symptoms of retinitis pigmentosa, as well as macular changes, suggestive of retinal pigment epithelium (RPE) involvement. The DHDDS enzyme is ubiquitously required for several pathways of protein glycosylation. We wish to understand the basis for selective ocular pathology associated with certain DHDDS mutations and the contribution of specific ocular cell types to the pathology of mutant Dhdds-mediated retinal degeneration. To circumvent embryonic lethality associated with Dhdds knockout, we generated a Cre-dependent knockout allele of murine Dhdds (Dhddsflx/flx). We used targeted Cre expression to study the importance of the enzyme in the RPE. Structural alterations of the RPE and retina including reduction in outer retinal thickness, cell layer disruption, and increased RPE hyper-reflectivity were apparent at one postnatal month. At three months, RPE and photoreceptor disruption was observed non-uniformly across the retina as well as RPE transmigration into the photoreceptor layer, external limiting membrane descent towards the RPE, and patchy loss of photoreceptors. Functional loss measured by electroretinography was consistent with structural loss showing scotopic a- and b-wave reductions of 83% and 77%, respectively, at three months. These results indicate that RPE dysfunction contributes to DHDDS mutation-mediated pathology and suggests a more complicated disease mechanism than simply disruption of glycosylation. View Full-Text
Keywords: retinal degeneration; retinitis pigmentosa; retinal pigment epithelium dystrophy; RPE transmigration; Cre-Lox technology; mouse models retinal degeneration; retinitis pigmentosa; retinal pigment epithelium dystrophy; RPE transmigration; Cre-Lox technology; mouse models
Show Figures

Figure 1

MDPI and ACS Style

DeRamus, M.L.; Davis, S.J.; Rao, S.R.; Nyankerh, C.; Stacks, D.; Kraft, T.W.; Fliesler, S.J.; Pittler, S.J. Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration. Cells 2020, 9, 771.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop