Mitogen- and stress-activated protein kinase 1 modulates photic entrainment of the suprachiasmatic circadian clock.
Mitogen- and stress-activated protein kinase 1 modulates photic entrainment of the suprachiasmatic circadian clock.
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DOI：
10.1111/ejn.12028
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Obrietan K
中科院分区：
文献类型：
--
作者：
Cao R;Butcher GQ;Karelina K;Arthur JS;Obrietan K
哺乳动物的主生物钟-视交叉上核(SCN)受到外部光周期的影响。在机制水平上，通过p42/44丝裂原活化蛋白激酶(MAPK)途径的细胞内信号似乎在光诱导的时钟携带中发挥核心作用；然而，该途径影响时钟计时的确切下游机制尚不清楚。在此背景下，我们已经报道了光刺激SCN中MAPK效应分子丝裂原应激激活激酶1(MSK1)的激活。在这项研究中，我们利用MSK1-/-小鼠进一步研究MSK1在生物钟计时和携带中的潜在作用。运动活动分析显示，MSK1基因缺失的小鼠经历了12h的光/暗周期，并在持续的黑暗中表现出昼夜自由奔跑的节律。有趣的是，MSK1缺失的小鼠的自由奔跑时间显著长于WT对照组动物，并且MSK1缺失的小鼠在活动开始方面表现出显著更大的差异。此外，MSK1基因缺失的小鼠表现出对早夜光脉冲(100勒克斯，15分钟)的相位延迟反应显著减少，并且，使用8小时相位推进的“时差”实验范式，MSK1基因敲除的小鼠表现出显著延迟的重新携带速率。在分子水平上，与WT小鼠相比，MSK1-/-动物夜间光照诱导的CREB磷酸化、组蛋白磷酸化和Perod1基因表达显著减弱。总之，这些数据为MSK1影响SCN时钟的分子机制提供了关键的新见解。
The master circadian clock in mammals, the suprachiasmatic nucleus (SCN), is under the entraining influence of the external light cycle. At a mechanistic level, intracellular signaling via the p42/44 mitogen-activated protein kinase (MAPK) pathway appears to play a central role in light-evoked clock entrainment; however, the precise downstream mechanisms by which this pathway influences clock timing are not known. Within this context, we have previously reported that light stimulates activation of the MAPK effector mitogen stress activated kinase 1 (MSK1) in the SCN. In this study we utilized MSK1-/- mice to further investigate the potential role of MSK1 in circadian clock timing and entrainment. Locomotor activity analysis revealed that MSK1 null mice entrained to a 12h light/dark cycle and exhibited circadian free-running rhythms in constant darkness. Interestingly, the free running period in MSK1 null mice was significantly longer than WT control animals, and MSK1 null mice exhibited a significantly greater variance in activity onset. Further, MSK1 null mice exhibited a significant reduction in the phase delaying response to an early night light pulse (100 lux, 15 min), and, using an 8-hr phase-advancing “jet-lag” experimental paradigm MSK1 knockout animals exhibited a significantly delayed rate of re-entrainment. At the molecular level, early night light-evoked CREB phosphorylation, histone phosphorylation and Period1 gene expression were markedly attenuated in MSK1-/- animals relative to WT mice. Together, these data provide key new insights into the molecular mechanisms by which MSK1 affects the SCN clock.
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