Clock and light regulation of the CREB coactivator CRTC1 in the suprachiasmatic circadian clock.
Clock and light regulation of the CREB coactivator CRTC1 in the suprachiasmatic circadian clock.
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DOI：
10.1523/jneurosci.4202-12.2013
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发表时间：
2013-05-22
期刊：
影响因子：
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通讯作者：
Obrietan K
中科院分区：
文献类型：
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作者：
Sakamoto K;Norona FE;Alzate-Correa D;Scarberry D;Hoyt KR;Obrietan K
CREB/CRE转录途径与生物钟计时和光诱发的生物钟重置有关。到目前为止，CREB在昼夜生理学中的大部分工作都集中在CREB磷酸化状态的变化如何调节时序过程。然而，除了磷酸化的变化之外，CREB依赖性转录也可以由CREB共激活因子CRTC（CREB调节转录共激活因子）调节，也称为TORC（调节CREB的转导子）。在这里，我们分析了CRTC 1和CRTC 2在小鼠视交叉上核（SCN），主哺乳动物时钟的位点的节奏和光诱发的调节。免疫组化显示SCN中CRTC 1的节律性表达。CRTC 1的表达检测到整个背腹侧的SCN在中间的主观一天，有限的表达在夜间早期，和深夜的表达水平中间的中午和夜间早期的水平。与CRTC 1相反，CRTC 2的稳健表达在主观的白天和夜晚都被检测到。在早期和后期主观的夜晚，一个简短的光脉冲诱导强烈的核积累的CRTC 1的SCN。与CRTC 1相反，光刺激不影响CRTC 2在SCN中的亚细胞定位。此外，period 1报告基因分析和ChIP分析显示，CRTC 1与CREB在period 1基因的5′调控区相关，CRTC 1的过表达导致period 1转录显著上调。这些数据共同提出了CRTC 1在SCN时钟定时和夹带的基本方面发挥作用的前景。
The CREB/CRE transcriptional pathway has been implicated in circadian clock timing and light-evoked clock resetting. To date, much of the work on CREB in circadian physiology has focused on how changes in the phosphorylation state of CREB regulate the timing processes. However, beyond changes in phosphorylation, CREB-dependent transcription can also be regulated by the CREB co-activator CRTC (CREB-regulated transcription coactivator), also known as TORC (Transducer of Regulated CREB). Here we profiled both the rhythmic and light-evoked regulation of CRTC1 and CRTC2 in the murine suprachiasmatic nucleus (SCN), the locus of the master mammalian clock. Immunohistochemical analysis revealed rhythmic expression of CRTC1 in the SCN. CRTC1 expression was detected throughout the dorso-ventral extent of the SCN in the middle of the subjective day, with limited expression during early night, and late night expression levels intermediate between mid-day and early night levels. In contrast to CRTC1, robust expression of CRTC2 was detected during both the subjective day and night. During early and late subjective night, a brief light pulse induced strong nuclear accumulation of CRTC1 in the SCN. In contrast with CRTC1, photic stimulation did not affect the subcellular localization of CRTC2 in the SCN. Additionally, period1 reporter gene profiling and ChIP analysis revealed that CRTC1 was associated with CREB in the 5′ regulatory region of the period1 gene, and that over-expression of CRTC1 leads to a marked upregulation in period1 transcription. Together these data raise the prospect that CRTC1 plays a role in fundamental aspects of SCN clock timing and entrainment.