The Phosphorylation of CREB at Serine 133 Is a Key Event for Circadian Clock Timing and Entrainment in the Suprachiasmatic Nucleus.
The Phosphorylation of CREB at Serine 133 Is a Key Event for Circadian Clock Timing and Entrainment in the Suprachiasmatic Nucleus.
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DOI：
10.1177/0748730418791713
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发表时间：
2018-10
影响因子：
3.5
通讯作者：
Obrietan K
中科院分区：
文献类型：
--
作者：
Wheaton KL;Hansen KF;Aten S;Sullivan KA;Yoon H;Hoyt KR;Obrietan K
在视交叉上核（SCN）-主昼夜节律钟的位点-通过CREB/CRE途径的转录调节涉及分子时钟计时过程的功能，并且是光输入夹带振荡器的关键管道。驱动CREB介导的转录的一个事件是CREB在丝氨酸133（Ser 133）处的磷酸化。事实上，许多报告基因测定已经表明，Ser 133中的丙氨酸点突变减少CREB介导的转录。在这里，我们试图研究Ser 133磷酸化的贡献，CREB在SCN时钟生理学在体内的功能作用。为此，我们使用CREB基因敲入小鼠品系，其中Ser 133突变为丙氨酸（S/A CREB）。在一个标准的12小时的光-暗周期，S/A CREB小鼠表现出明显的改变，在时钟调节轮运行活动。相对于WT小鼠，S/A CREB小鼠在夜间阶段具有高度碎片化的运动活动，白天活动增加，以及延迟的夹带相角。此外，在自由奔跑条件下，S/A CREB小鼠具有比WT小鼠显著更长的tau和降低的活动幅度。在S/A CREB小鼠中，相对于WT小鼠，使用Aschoff 1型和6小时“时差”范式的光诱发的时钟诱导显着减少。S/A CREB小鼠表现出衰减的转录驱动，通过检查时钟门控和光诱发的基因表达进行评估。最后，SCN切片培养成像检测到S/A CREB小鼠在相位重置刺激后细胞时钟相位同步的显著中断。总之，这些数据表明，通过CREB在Ser 133磷酸化的信号传导对于SCN定时和夹带的功能保真度至关重要。
Within the suprachiasmatic nucleus (SCN)—the locus of the master circadian clock— transcriptional regulation via the CREB/CRE pathway is implicated in the functioning of the molecular clock timing process, and is a key conduit through which photic input entrains the oscillator. One event driving CRE-mediated transcription is the phosphorylation of CREB at serine 133 (Ser133). Indeed, numerous reporter gene assays have shown that an alanine point mutation in Ser133 reduces CREB-mediated transcription. Here, we sought to examine the contribution of Ser133 phosphorylation to the functional role of CREB in SCN clock physiology in vivo. To this end, we used a CREB knock-in mouse strain, in which Ser133 was mutated to alanine (S/A CREB). Under a standard 12 h light-dark cycle, S/A CREB mice exhibited a marked alteration in clock-regulated wheel running activity. Relative to WT mice, S/A CREB mice had highly fragmented bouts of locomotor activity during the night phase, elevated daytime activity, and a delayed phase angle of entrainment. Further, under free-running conditions, S/A CREB mice had a significantly longer tau than WT mice and reduced activity amplitude. In S/A CREB mice, light-evoked clock entrainment, using both Aschoff type 1 and 6 h “jet lag” paradigms, was markedly reduced relative to WT mice. S/A CREB mice exhibited attenuated transcriptional drive, as assessed by examining both clock-gated and light-evoked gene expression. Finally, SCN slice culture imaging detected a marked disruption in cellular clock phase synchrony following a phase-resetting stimulus in S/A CREB mice. Together, these data indicate that signaling through CREB phosphorylation at Ser133 is critical for the functional fidelity of both SCN timing and entrainment.
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DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.5
作者：
Arthur, JSC;Cohen, P
通讯作者：
Cohen, P
影响因子：
5.3
作者：
Gandolfi D;Cerri S;Mapelli J;Polimeni M;Tritto S;Fuzzati-Armentero MT;Bigiani A;Blandini F;Mapelli L;D'Angelo E
通讯作者：
D'Angelo E
影响因子：
3.3
作者：
Chan, JYH;Chen, WC;Chan, SHH
通讯作者：
Chan, SHH
影响因子：
16.6
作者：
Doi, Masao;Ishida, Atsushi;Miyake, Akiko;Sato, Miho;Komatsu, Rie;Yamazaki, Fumiyoshi;Kimura, Ikuo;Tsuchiya, Soken;Kori, Hiroshi;Seo, Kazuyuki;Yamaguchi, Yoshiaki;Matsuo, Masahiro;Fustin, Jean-Michel;Tanaka, Rina;Santo, Yasuko;Yamada, Hiroyuki;Takahashi, Yukari;Araki, Michihiro;Nakao, Kazuki;Aizawa, Shinichi;Kobayashi, Masaki;Obrietan, Karl;Tsujimoto, Gozoh;Okamura, Hitoshi
通讯作者：
Okamura, Hitoshi