Joo Jae-Yeol, Schaukowitch Katie, Farbiak Lukas, Kilaru Gokhul, Kim Tae-Kyung
Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Nat Neurosci. 2016 Jan;19(1):75-83. doi: 10.1038/nn.4170. Epub 2015 Nov 23.
The c-fos gene (also known as Fos) is induced by a broad range of stimuli and is a reliable marker for neural activity. Its induction mechanism and available reporter mouse lines are based exclusively on c-fos promoter activity. Here we demonstrate that multiple enhancers surrounding the c-fos gene are crucial 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.
c-fos基因（也称为Fos）可被多种刺激诱导，是神经活动的可靠标志物。其诱导机制和现有的报告基因小鼠品系完全基于c-fos启动子活性。在此，我们证明c-fos基因周围的多个增强子对于确保对各种刺激产生强大的c-fos反应至关重要。膜去极化、脑源性神经营养因子（BDNF）和福斯高林激活不同的增强子亚群，以诱导神经元中的c-fos转录，这表明多个增强子的刺激特异性组合激活是c-fos基因广泛诱导性的基础。因此，关键转录因子的功能需求因刺激类型而异。组合增强子激活也发生在大脑中。我们的研究提供了超越最小启动子的c-fos诱导机制的全面图景，应有助于理解与神经活动和可塑性相关的c-fos诱导的生理本质。
