Stimulus-specific combinatorial functionality of neuronal c-fos enhancers.
Stimulus-specific combinatorial functionality of neuronal c-fos enhancers.
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DOI：
10.1038/nn.4170
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发表时间：
2016-01
影响因子：
25
通讯作者：
Kim TK
中科院分区：
文献类型：
--
作者：
Joo JY;Schaukowitch K;Farbiak L;Kilaru G;Kim TK
c-fos基因可被广泛的刺激所诱导，并且通常被用作神经活动的可靠标记。其诱导机制和可用的报告小鼠系完全基于c-fos启动子活性。在这里，我们表明，多个增强子周围的c-fos基因是至关重要的，以确保强大的c-fos对各种刺激的反应。膜去极化，脑源性神经营养因子（BDNF），和毛喉素激活不同的子集的增强子，诱导c-fos在神经元中的转录，这表明刺激特异性组合激活的多个增强子的c-fos基因的广泛诱导的基础。因此，关键转录因子的功能需求根据刺激的类型而变化。组合增强子激活也发生在大脑中。提供了一个全面的图片的c-fos诱导机制超出最小的启动子，我们的研究应该有助于了解c-fos诱导神经活动和可塑性的生理性质。
The c-fos gene is induced by a broad range of stimuli, and has been commonly used as a reliable marker for neural activity. Its induction mechanism and available reporter mouse lines are exclusively based on the c-fos promoter activity. Here, we demonstrate that multiple enhancers surrounding the c-fos gene are critical for ensuring robust c-fos response to various stimuli. Membrane depolarization, brain-derived neurotrophic factor (BDNF), and Forskolin activate distinct subsets of the enhancers to induce c-fos transcription in neurons, suggesting that stimulus-specific combinatorial activation of multiple enhancers underlies the broad inducibility of the c-fos gene. Accordingly, the functional requirement of key transcription factors varies depending on the type of stimulation. Combinatorial enhancer activation also occurs in the brain. Providing a comprehensive picture of the c-fos induction mechanism beyond the minimal promoter, our study should help in understanding the physiological nature of c-fos induction in relation to neural activity and plasticity.