Crosstalk Between Glucocorticoid Receptor and Early-growth Response Protein 1 Accounts for Repression of Brain-derived Neurotrophic Factor Transcript 4 Expression
Crosstalk Between Glucocorticoid Receptor and Early-growth Response Protein 1 Accounts for Repression of Brain-derived Neurotrophic Factor Transcript 4 Expression
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DOI：
10.1016/j.neuroscience.2018.12.012
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发表时间：
2019-02-10
期刊：
影响因子：
3.3
通讯作者：
Le Menuet, Damien
中科院分区：
文献类型：
--
作者：
Chen, Hui;Amazit, Larbi;Le Menuet, Damien
脑源性神经营养因子（BDNF）是脑功能的关键参与者，如突触可塑性，压力和行为。其在啮齿动物中的基因结构包含8个非翻译外显子（I至VIII），其表达受到精细调控，并剪接到共同且独特的翻译外显子IX上。BDNF表达的改变与许多病理学相关，如抑郁症、阿尔茨海默病和成瘾。糖皮质激素通过与糖皮质激素受体（GR）结合，在应激反应、情绪和神经元可塑性等方面发挥重要作用。我们最近发现，在神经元原代培养和永生化的神经元样BZ细胞，GR抑制BDNF的表达，特别是BDNF的外显子IV含有mRNA亚型（Bdnf 4）通过GR结合到一个短的275 bp序列的BDNF启动子。在此，我们通过瞬时转染实验和BZ细胞中的诱变，证明GR与位于BDNF外显子IV启动子的转录起始位点的早期生长反应蛋白1（EGR 1）反应元件（EGR-RE）相互作用。使用染色质免疫沉淀，我们发现，GR和EGR 1结合到这个启动子序列中的糖皮质激素依赖的方式，并通过共免疫沉淀表明，GR和EGR 1的物理相互作用。有趣的是，EGR 1被广泛认为是大脑可塑性的调节因子。总之，我们破译了GR下调BDNF表达的机制，确定了糖皮质激素途径，立即早期生长反应蛋白和BDNF之间的新功能串扰。由于所有这些因素都与脑病理生理学密切相关，因此这些发现可能在神经科学和治疗学方面具有重要意义。(C)2018年IBRO。由爱思唯尔有限公司出版。保留所有权利。
The brain-derived neurotrophic factor (BDNF) is a key player in brain functions such as synaptic plasticity, stress, and behavior. Its gene structure in rodents contains 8 untranslated exons (I to VIII) whose expression is finely regulated and which spliced onto a common and unique translated exon IX. Altered Bdnf expression is associated with many pathologies such as depression, Alzheimer's disease and addiction. Through binding to glucocorticoid receptor (GR), glucocorticoids play a pivotal role for stress responses, mood and neuronal plasticity. We recently showed in neuronal primary culture and in the immortalized neuronal-like BZ cells that GR repressed Bdnf expression, notably the bdnf exon IV containing mRNA isoform (Bdnf4) via GR binding to a short 275-bp sequence of Bdnf promoter. Herein, we demonstrate by transient transfection experiments and mutagenesis in BZ cells that GR interacts with an early growth response protein 1 (EGR1) response element (EGR-RE) located in the transcription start site of Bdnf exon IV promoter. Using Chromatin Immunoprecipitation, we find that both GR and EGR1 bind to this promoter sequence in a glucocorticoid-dependent manner and demonstrate by co-immunoprecipitation that GR and EGR1 are interacting physically. Interestingly, EGR1 has been widely characterized as a regulator of brain plasticity. In conclusion, we deciphered a mechanism by which GR downregulates Bdnf expression, identifying a novel functional crosstalk between glucocorticoid pathways, immediate early growth response proteins and Bdnf. As all these factors are well-recognized germane for brain pathophysiology, these findings may have significant implications in neurosciences as well as in therapeutics. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.