1. Glucocorticoid receptor and myocyte enhancer factor 2 cooperate to regulate the expression of c-JUN in a neuronal context.
- Author
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Speksnijder N, Christensen KV, Didriksen M, De Kloet ER, and Datson NA
- Subjects
- Animals, Animals, Newborn, Dexamethasone pharmacology, Down-Regulation drug effects, Down-Regulation physiology, Gene Expression Regulation drug effects, Gene Expression Regulation physiology, Gene Knockdown Techniques, Glucocorticoids pharmacology, Hippocampus cytology, MADS Domain Proteins genetics, MEF2 Transcription Factors, Mice, Mice, Inbred Strains, Myogenic Regulatory Factors genetics, Neuronal Plasticity physiology, Neurons cytology, Neurons drug effects, PC12 Cells, Phosphorylation physiology, Proto-Oncogene Proteins c-jun metabolism, Rats, Receptors, Glucocorticoid genetics, MADS Domain Proteins metabolism, Myogenic Regulatory Factors metabolism, Neurons physiology, Proto-Oncogene Proteins c-jun genetics, Receptors, Glucocorticoid metabolism
- Abstract
The glucocorticoid receptor (GR) and myocyte enhancer factor 2 (MEF2) are transcription factors involved in neuronal plasticity. c-JUN, a target gene of GR and MEF2, plays a role in regulating both synaptic strength and synapse number. The aim of this study was to investigate the nature of this dual regulation of c-JUN by GR and MEF2 in a neuronal context. First, we showed that GR mediates the dexamethasone-induced suppression of c-JUN mRNA expression. Next, we observed that GR activation resulted in an increase in phosphorylation of MEF2, a post-translational modification known to change MEF2 from a transcriptional enhancer to a repressor. In addition, we observed an enhanced binding of MEF2 to genomic sites directly upstream of the c-JUN gene upon GR activation. Finally, in primary hippocampal neuronal cultures, knockdown of MEF2 not only reduced c-JUN expression levels but abolished GR regulation of c-JUN expression. This suggests that MEF2 is necessary for GR regulation of c-JUN. In conclusion, for the first time, we show that activated GR requires MEF2 to regulate c-JUN. At the same time, GR influences MEF2 activity and DNA binding. These results give novel insight into the molecular interplay of GR and MEF2 in the control of genes important for neuronal plasticity.
- Published
- 2012
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