title: Glucocorticoid receptor and myocyte enhancer factor 2 cooperate to regulate the expression of c-JUN in a neuronal context.
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.
authors.affiliation: Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research (LACDR), Leiden University Medical Center, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Speksnijder
authors.forename: Kenneth V
authors.initials: KV
authors.lastname: Christensen
authors.forename: Michael
authors.initials: M
authors.lastname: Didriksen
authors.forename: E Ronald
authors.initials: ER
authors.lastname: De Kloet
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Datson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D005938:Glucocorticoids / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D026161:MADS Domain Proteins / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D008815:Mice, Inbred Strains; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D010766:Phosphorylation / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578037:MEF2A protein, rat; D018006:Myogenic Regulatory Factors; D016755:Proto-Oncogene Proteins c-jun; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone