The Role of MEF2 transcription factors in retinal ganglion cell survival and axon regeneration

Abstract

Purpose : What is the function of myocyte enhancer factor 2 (MEF2) signaling pathways in retinal ganglion cell (RGC) survival and axon regeneration following axon injury? MEF2A and MEF2D are the primary MEF2 isoforms expressed in RGCs and other retinal neuronal cell types. It was recently reported MEF2A knockout enhances RGC survival. Here we explore MEF2 isoforms and point mutants in RGC survival and axon regeneration in vivo.

Methods : We subjected conditional mef2a/c/d triple knockout, mef2a/d double knockout and mef2d knockout mice to optic nerve crush to study MEF2’s effects on neuron protection and regeneration. In some experiments, AAV expression vectors for flag-tagged wildtype and mutant MEF2D proteins were intravitreally injected into the eyes of mef2a/d double knockout mice. Expression of gene and protein were detected by quantitative PCR, immustaining and western blot.

Results : Mef2a/c/d triple knockout and mef2a/d double knockout, but not mef2d knockout alone, increased RGC survival after ONC but showed no change in axon regeneration. On the mef2a/d double knockout background, MEF2D wildtype and mutant proteins didn’t show any pro-survival function, except MEF2D S444A mutant improved axon growth after optic nerve crush in vivo which was consistent with our previous in vitro work showing this activating mutation promoted neurite extension in primary neurons.

Conclusions : Depletion of MEF2 transcriptional regulatory genes, and probably mainly MEF2A, increases RGC survival, whereas MEF2D S444A mutant proteins enhance axon regeneration in vivo.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.