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MEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury
- 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.
- Subjects :
- Retinal Ganglion Cells
0301 basic medicine
genetic structures
Gene Expression
Cell Count
Biochemistry
Mice
Nerve Fibers
0302 clinical medicine
Animal Cells
Medicine and Health Sciences
MEF2C
Axon
Neurons
Multidisciplinary
MEF2 Transcription Factors
Animal Models
Cell biology
medicine.anatomical_structure
Experimental Organism Systems
Retinal ganglion cell
Gene Targeting
Optic nerve
Crush injury
Medicine
Cellular Types
Anatomy
Signal Transduction
Research Article
Ganglion Cells
Ocular Anatomy
Science
Mouse Models
Biology
Research and Analysis Methods
Retinal ganglion
Neuroprotection
Retina
03 medical and health sciences
Model Organisms
Ocular System
DNA-binding proteins
Genetics
medicine
Animals
Humans
Point Mutation
Gene Regulation
Molecular Biology Techniques
Molecular Biology
Alleles
Biology and Life Sciences
Afferent Neurons
Proteins
Optic Nerve
Cell Biology
medicine.disease
Axons
eye diseases
Regulatory Proteins
030104 developmental biology
Optic Nerve Injuries
Cellular Neuroscience
Artificial Genetic Recombination
Animal Studies
sense organs
030217 neurology & neurosurgery
Neuroscience
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 15
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....39651a883d2040c30b26e54c9baac3e9