Altered Rhythm of Adrenal Clock Genes, StAR and Serum Corticosterone in VIP Receptor 2-Deficient Mice
Altered Rhythm of Adrenal Clock Genes, StAR and Serum Corticosterone in VIP Receptor 2-Deficient Mice
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DOI：
10.1007/s12031-012-9804-7
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发表时间：
2012-11-01
影响因子：
3.1
通讯作者：
Jorgensen, Henrik Lovendahl
中科院分区：
文献类型：
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作者：
Fahrenkrug, Jan;Georg, Birgitte;Jorgensen, Henrik Lovendahl
昼夜节律计时系统由视交叉上核（SCN）和外周器官中的时钟组成，包括通过调节类固醇生成急性调节蛋白（StAR）与节律性皮质类固醇产生相关的肾上腺时钟。时钟细胞包含一个自主的分子振荡器，它基于一组时钟基因及其蛋白质产物。缺乏VPAC 2受体展示的小鼠扰乱了生理和行为的昼夜节律，因此，我们使用实时RT-PCR定量（1）肾上腺和SCN中时钟基因Per1和Bmal 1的mRNA，（2）肾上腺星星mRNA和（3）在光/暗（L/D）循环期间和在野生型（WT）中恒定黑暗时的血清皮质酮浓度，以及VPAC 2受体-缺陷型小鼠（VPAC 2-KO）。我们还检查了PER1和StAR是否共同定位在肾上腺类固醇生成细胞中。Per1和Bmal1 mRNA在WT小鼠肾上腺中的表达在L/D和黑暗条件下显示出24小时的节律性。在L/D周期中，与WT小鼠相比，VPAC 2-KO小鼠中的肾上腺时钟基因节律相位提前约6小时，并且在恒定黑暗中变得缓慢。肾上腺星星mRNA表达和循环皮质酮浓度的显著24小时节律变化在L/D周期中也具有类似的相位提前。VPAC 2受体敲除小鼠转移到恒定黑暗后肾上腺时钟基因节律的丧失伴随着星星mRNA表达和血清皮质酮浓度的节律性消失。双重免疫组化显示PER1蛋白和StAR共定位于相同的类固醇生成细胞中。循环皮质酮在昼夜节律系统中起作用，VPAC 2受体敲除小鼠中的失调皮质酮节律可能参与其异常的生理节律。
The circadian time-keeping system consists of clocks in the suprachiasmatic nucleus (SCN) and in peripheral organs including an adrenal clock linked to the rhythmic corticosteroid production by regulating steroidogenic acute regulatory protein (StAR). Clock cells contain an autonomous molecular oscillator based on a group of clock genes and their protein products. Mice lacking the VPAC2 receptor display disrupted circadian rhythm of physiology and behaviour, and therefore, we using real-time RT-PCR quantified (1) the mRNAs for the clock genes Per1 and Bmal1 in the adrenal gland and SCN, (2) the adrenal Star mRNA and (3) the serum corticosterone concentration both during a light/dark (L/D) cycle and at constant darkness in wild type (WT) and VPAC2 receptor-deficient mice (VPAC2-KO). We also examined if PER1 and StAR were co-localised in the adrenal steroidogenic cells. Per1 and Bmal1 mRNA showed a 24-h rhythmic expression in the adrenal of WT mice under L/D and dark conditions. During a L/D cycle, the adrenal clock gene rhythm in VPAC2-KO mice was phase-advanced by approximately 6 h compared to WT mice and became arrhythmic in constant darkness. A significant 24-h rhythmic variation in the adrenal Star mRNA expression and circulating corticosterone concentration was similarly phase-advanced during the L/D cycle. The loss of adrenal clock gene rhythm in the VPAC2 receptor knockout mice after transfer into constant darkness was accompanied by disappearance of rhythmicity in Star mRNA expression and serum corticosterone concentration. Double immunohistochemistry showed that the PER1 protein and StAR were co-localised in the same steroidogenic cells. Circulating corticosterone plays a role in the circadian timing system and the misaligned corticosterone rhythm in the VPAC2 receptor knockout mice could be involved in their abnormal rhythms of physiology.