Molecular Pathway to Protection From Age-Dependent Photoreceptor Degeneration in Mef2 Deficiency

Abstract

PurposePhotoreceptor 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.MethodsWe 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.ResultsWe identify a prosurvival MEF2D-PGC1α pathway that plays a neuroprotective role in photoreceptors. We demonstrate that Mef2d−/− mouse retinas manifest decreased expression of PGC1α and increased photoreceptor cell loss, resulting in the absence of light responses. Molecular repletion of PGC1α protects Mef2d−/− photoreceptors and preserves light responsivity.ConclusionsThese results suggest that the MEF2-PGC1α cascade may represent a new therapeutic target for drugs designed to protect photoreceptors from developmental- and age-dependent loss.

Intravitreal Delivery of Melatonin Is Protective Against the Photoreceptor Loss in Mice: A Potential Therapeutic Strategy for Degenerative Retinopathy

“…Oxidative stress in turn activates the apoptotic cascade, and accelerates the death of photoreceptors (Talcott et al, 2011). TUNEL assay is a reliable method to identify the apoptotic cells in retina (Nagar et al, 2017). Our TUNEL results show that intravitreal injection of melatonin is able to inhibit the MNU induced photoreceptor apoptosis.…”

A novel transcript of MEF2D promotes myoblast differentiation and its variations associated with growth traits in chicken

“…The position and sequence of exon 4 of the transcript MEF2D-V4 was different from that of the original transcript MEF2D-1, that is, the AA sequence 87-132 was different. The mutation region of this new transcript was similar to the variant transcript found in humans and mice, and they were both mutated in the AA sequence 87-132 region (Edmondson et al, 1994;Ornatsky & McDermott, 1996;Nagar et al, 2017). The human variant transcript Mef2Da2 is expressed specifically in muscle, and it can avoid inhibitory phosphorylation, recruit Ash2L to activate muscle-related genes, and promote muscle cell differentiation (Sebastian et al, 2013).…”

Optimized nonionic emulsifier for the efficient delivery of astaxanthin nanodispersions to retina: in vivo and ex vivo evaluations

“…On the other hand, oxidative stress in turn activates the apoptotic cascade, and accelerates the destruction of photoreceptors (Campochiaro & Mir, 2018). Generally, TUNEL assay acts a reliable method to identify the apoptotic cells and quantify the apoptotic levels in retinas (Nagar et al., 2017). We find that AST nanodispersions can reduce significantly the mRNA level of Caspase-3, which acts as a classic mediator in photoreceptor apoptosis.…”