Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research (LACDR), Leiden University Medical Center, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.
J Mol Neurosci. 2012 Sep;48(1):209-18. doi: 10.1007/s12031-012-9809-2. Epub 2012 May 24.
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.
糖皮质激素受体 (GR) 和肌细胞增强因子 2 (MEF2) 是参与神经元可塑性的转录因子。c-JUN 是 GR 和 MEF2 的靶基因，在调节突触强度和突触数量方面发挥作用。本研究旨在探讨 GR 和 MEF2 在神经元环境中对 c-JUN 的这种双重调节的性质。首先，我们表明 GR 介导了地塞米松诱导的 c-JUN mRNA 表达抑制。接下来，我们观察到 GR 激活导致 MEF2 的磷酸化增加，这种翻译后修饰已知可将 MEF2 从转录增强子转变为抑制剂。此外，我们观察到 GR 激活后，c-JUN 基因上游的 MEF2 与基因组位点的结合增强。最后，在原代海马神经元培养物中，MEF2 的敲低不仅降低了 c-JUN 的表达水平，而且消除了 GR 对 c-JUN 表达的调节。这表明 MEF2 是 GR 调节 c-JUN 所必需的。总之，我们首次表明激活的 GR 需要 MEF2 来调节 c-JUN。同时，GR 影响 MEF2 的活性和 DNA 结合。这些结果为 GR 和 MEF2 在控制神经元可塑性重要基因方面的分子相互作用提供了新的见解。
