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MEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury

Authors :
Jeffrey L. Goldberg
Sahil Shah
Minjuan Bian
Kun-Che Chang
Bogdan Tanasa
Xin Xia
Hrishikesh Thakur
Dawn M. Bruffett
Catalina B. Sun
Evan G. Cameron
Caroline Yu
Michael S. Kapiloff
Cara Knasel
Source :
PLoS ONE, Vol 15, Iss 12, p e0242884 (2020), PLoS ONE
Publication Year :
2020
Publisher :
Public Library of Science (PLoS), 2020.

Abstract

Loss of retinal ganglion cells (RGCs) in optic neuropathies results in permanent partial or complete blindness. Myocyte enhancer factor 2 (MEF2) transcription factors have been shown to play a pivotal role in neuronal systems, and in particular MEF2A knockout was shown to enhance RGC survival after optic nerve crush injury. Here we expanded these prior data to study bi-allelic, tri-allelic and heterozygous allele deletion. We observed that deletion of all MEF2A, MEF2C, and MEF2D alleles had no effect on RGC survival during development. Our extended experiments suggest that the majority of the neuroprotective effect was conferred by complete deletion of MEF2A but that MEF2D knockout, although not sufficient to increase RGC survival on its own, increased the positive effect of MEF2A knockout. Conversely, MEF2A over-expression in wildtype mice worsened RGC survival after optic nerve crush. Interestingly, MEF2 transcription factors are regulated by post-translational modification, including by calcineurin-catalyzed dephosphorylation of MEF2A Ser-408 known to increase MEF2A-dependent transactivation in neurons. However, neither phospho-mimetic nor phospho-ablative mutation of MEF2A Ser-408 affected the ability of MEF2A to promote RGC deathin vivoafter optic nerve injury. Together these findings demonstrate that MEF2 gene expression opposes RGC survival following axon injury in a complex hierarchy, and further support the hypothesis that loss of or interference with MEF2A expression might be beneficial for RGC neuroprotection in diseases such as glaucoma and other optic neuropathies.

Details

Language :
English
ISSN :
19326203
Volume :
15
Issue :
12
Database :
OpenAIRE
Journal :
PLoS ONE
Accession number :
edsair.doi.dedup.....39651a883d2040c30b26e54c9baac3e9