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ABSTRACT: Purpose
Photoreceptor degeneration in the retina is a major cause of blindness in humans. Elucidating mechanisms of degenerative and neuroprotective pathways in photoreceptors should afford identification and development of therapeutic strategies.Methods
We used mouse genetic models and improved methods for retinal explant cultures. Retinas were enucleated from Mef2d+/+ and Mef2d-/- mice, stained for MEF2 proteins and outer nuclear layer thickness, and assayed for apoptotic cells. Chromatin immunoprecipitation (ChIP) assays revealed MEF2 binding, and RT-qPCR showed levels of transcription factors. We used AAV2 and electroporation to express genes in retinal explants and electroretinograms to assess photoreceptor functionality.Results
We identify a prosurvival MEF2D-PGC1? pathway that plays a neuroprotective role in photoreceptors. We demonstrate that Mef2d-/- mouse retinas manifest decreased expression of PGC1? and increased photoreceptor cell loss, resulting in the absence of light responses. Molecular repletion of PGC1? protects Mef2d-/- photoreceptors and preserves light responsivity.Conclusions
These results suggest that the MEF2-PGC1? cascade may represent a new therapeutic target for drugs designed to protect photoreceptors from developmental- and age-dependent loss.
SUBMITTER: Nagar S
PROVIDER: S-EPMC5525556 | biostudies-literature | 2017 Jul
REPOSITORIES: biostudies-literature
Investigative ophthalmology & visual science 20170701 9
<h4>Purpose</h4>Photoreceptor degeneration in the retina is a major cause of blindness in humans. Elucidating mechanisms of degenerative and neuroprotective pathways in photoreceptors should afford identification and development of therapeutic strategies.<h4>Methods</h4>We used mouse genetic models and improved methods for retinal explant cultures. Retinas were enucleated from Mef2d+/+ and Mef2d-/- mice, stained for MEF2 proteins and outer nuclear layer thickness, and assayed for apoptotic cells ...[more]