Members of the myocyte enhancer factor 2 transcription factor family differentially regulate Bdnf transcription in response to neuronal depolarization.
Members of the myocyte enhancer factor 2 transcription factor family differentially regulate Bdnf transcription in response to neuronal depolarization.
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DOI：
10.1523/jneurosci.0534-12.2012
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发表时间：
2012-09-12
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影响因子：
--
通讯作者：
West AE
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文献类型：
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作者：
Lyons MR;Schwarz CM;West AE
脑源性神经营养因子 (Bdnf) 的转录是通过激活一系列复杂的转录因子来响应多种细胞外刺激而诱导的。然而，单个转录因子在多大程度上赋予 Bdnf 调节特异性尚不清楚。先前的研究表明，肌细胞增强因子 2 (MEF2) 转录因子家族的成员与 Bdnf 启动子 I 上游的调节元件结合，并与 Bdnf 启动子 IV 中的未知结合位点相关。在这里，我们确定了钙反应元件 CaRE1 作为 Bdnf 基因启动子 IV 中的 MEF2 结合位点，并确定了 Bdnf 调节中各个 MEF2 家族成员的要求。 MEF2A、C 和 D 在胚胎大鼠皮质神经元中均高度表达，但只有 Mef2c 基因编码缺乏 γ 阻遏结构域的 MEF2 剪接变体。我们发现缺乏γ结构域的MEF2C变体对膜去极化的激活特别敏感，这提高了MEF2可能对活性调节基因表达有不同贡献的可能性。我们发现，只有 MEF2C 的敲低才会显着损害膜去极化诱导的 Bdnf 外显子 IV 的表达。相比之下，MEF2D 的敲低显着增强了 Bdnf 外显子 I 的去极化诱导表达。总之，这些数据表明 MEF2 转录因子家族的各个成员差异性地调节 Bdnf 的表达，揭示了一种新机制，可能赋予这一重要生物学基因的诱导特异性。
Transcription of Brain-derived neurotrophic factor (Bdnf) is induced in response to a wide variety of extracellular stimuli via the activation of a complex array of transcription factors. However, to what degree individual transcription factors confer specificity upon the regulation of Bdnf is poorly understood. Previous studies have shown that members of the Myocyte Enhancer Factor 2 (MEF2) transcription factor family bind a regulatory element upstream of Bdnf promoter I and associate with an unknown binding site in Bdnf promoter IV. Here we identify the calcium-response element CaRE1 as the MEF2 binding site in promoter IV of the Bdnf gene and determine the requirements for individual MEF2 family members in Bdnf regulation. MEF2A, C, and D are all highly expressed in embryonic rat cortical neurons, however only the Mef2c gene encodes a MEF2 splice variant that lacks the γ repressor domain. We find that MEF2C variants lacking the γ-domain are particularly sensitive to activation by membrane depolarization, raising the possibility that the MEF2s may differentially contribute to activity-regulated gene expression. We find that only knockdown of MEF2C significantly impairs membrane depolarization-induced expression of Bdnf exon IV. By contrast, knockdown of MEF2D significantly enhanced depolarization-induced expression of Bdnf exon I. Taken together, these data show that individual members of the MEF2 family of transcription factors differentially regulate the expression of Bdnf, revealing a new mechanism that may confer specificity on the induction of this biologically important gene.