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In the mammalian nervous system, regulation of transcription factor activity is a crucial determinant of neuronal cell survival, differentiation, and death. The myocyte enhancer factor 2 (MEF2) transcription factors have been implicated in cellular processes underlying neuronal survival and differentiation. A core component of the MEF2 complex is the MEF2D subunit. Recently, we reported that cAMP-dependent protein kinase (cAMP/PKA) signaling negatively regulates MEF2D function in myogenic cells. Here, we assessed whether cAMP signaling converges on the prosurvival role of MEF2D in Sprague Dawley rat embryonic (E18) hippocampal neurons. Initially, we observed that experimental induction of cAMP/PKA signaling promotes apoptosis in primary hippocampal neurons as indicated by TUNEL and FACS analysis. Luciferase reporter gene assays revealed that PKA potently represses MEF2D trans-activation properties in neurons. This effect was largely reversed by engineered neutralizing mutations of PKA phospho-acceptor sites on MEF2D (S121/190A). Krüppel-like factor 6 (KLF6) was identified as a key transcriptional target of MEF2 in hippocampal neurons, and siRNA-mediated knockdown of KLF6 expression promotes neuronal cell death and also antagonizes the prosurvival role of MEF2D. These observations have important implications for understanding the pathways controlling cell survival and death in the mammalian nervous system.

Suppression of a MEF2-KLF6 Survival Pathway by PKA Signaling Promotes Apoptosis in Embryonic Hippocampal Neurons