Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis

Proceedings of the National Academy of Sciences of the United States of America
Shu-Ichi OkamotoS A Lipton

Abstract

Myocyte enhancer factor-2 (MEF2) transcription factors are activated by p38 mitogen-activated protein kinase during neuronal and myogenic differentiation. Recent work has shown that stimulation of this pathway is antiapoptotic during development but proapoptotic in mature neurons exposed to excitotoxic or other stress. We now report that excitotoxic (N-methyl-D-aspartate) insults to mature cerebrocortical neurons activate caspase-3, -7, in turn cleaving MEF2A, C, and D isoforms. MEF2 cleavage fragments containing a truncated transactivation domain but preserved DNA-binding domain block MEF2 transcriptional activity via dominant interference. Transfection of constitutively active MEF2 (MEF2C-CA) rescues MEF2 transcriptional activity after N-methyl-D-aspartate insult and prevents neuronal apoptosis. Conversely, dominant-interfering MEF2 abrogates neuroprotection by MEF2C-CA. These results define a pathway to excitotoxic neuronal stress/apoptosis via caspase-catalyzed cleavage of MEF2. Additionally, we show that similar MEF2 cleavage fragments are generated in vivo during focal stroke damage. Hence, this pathway appears to have pathophysiological relevance in vivo.

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Citations

Oct 9, 2002·Current Opinion in Neurobiology·Philip Washbourne, A Kimberley McAllister
Jul 10, 2003·Current Opinion in Neurobiology·Karl DeisserothRichard W Tsien
Jan 21, 2006·Nature Reviews. Drug Discovery·Stuart A Lipton
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Jan 3, 2015·Progress in Neuro-psychopharmacology & Biological Psychiatry·Concetta CrisafulliAlessandro Serretti
Jul 28, 2016·Cellular Reprogramming·Shuling ShenXingmei Feng

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