Cryptochrome 1 as a state variable of the circadian clockwork of the suprachiasmatic nucleus: Evidence from translational switching.
Cryptochrome 1 as a state variable of the circadian clockwork of the suprachiasmatic nucleus: Evidence from translational switching.
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DOI：
10.1073/pnas.2203563119
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发表时间：
2022-08-23
影响因子：
11.1
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中科院分区：
文献类型：
--
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生物钟使我们适应有节奏的世界，为我们的生活设定节奏。因此，对他们的干扰（例如，倒班）造成了严重的健康损失。视交叉上核（SCN）是哺乳动物的主要大脑时钟，它的时间围绕一个延迟的基因和蛋白质表达的负反馈循环进行旋转。通过使用“翻译开关”作为可逆控制SCN器官型切片中负反馈调节因子Cryptochrome 1 （CRY1）表达的手段，我们发现CRY1水平的急性变化决定了昼夜节律时间。因此，我们将SCN时钟的理论和生化观点联系起来。下丘脑的视交叉上核（SCN）是驱动生理和行为昼夜节律的主要时钟，使哺乳动物适应环境周期。SCN依赖性节律的破坏会损害健康，因此了解SCN的计时将为现代生活方式相关疾病的管理提供信息。SCN时间保持是一个自我维持的转录/翻译延迟反馈回路（TTFL），负调控因子抑制其自身的转录。形式上，SCN时钟被视为一个极限环振荡器，最简单的是一个连续相位的轨迹，它在二维空间中发展，由两个状态变量沿着各自的轴映射。TTFL基序很容易与极限环模型兼容，并且在神经孢子虫和果蝇中，负调节因子频率（FRQ）和周期（Per）已被确定为各自TTFL的状态变量。然而，SCN振荡器的状态变量的同一性不太清楚。状态变量的实验识别需要对它们的丰度进行可逆和时间特定的控制。翻译开关（ts）提供了这一点，感兴趣的蛋白质的表达依赖于非规范氨基酸的提供。我们发现负调节因子Cryptochrome 1 （CRY1）满足定义状态变量的标准：ts-CRY1剂量依赖性和可逆地抑制SCN节律的基线、振幅和周期，其急性戒断释放TTFL从一个确定的阶段振荡。它的作用也取决于它的时间表达模式，尽管本构性ts-CRY1持续（尽管不太稳定）振荡。我们得出结论，CRY1具有状态变量的性质，但可以在多维极限环内的多个状态变量之间运行。
Circadian clocks adapt us to our rhythmic world, setting the tempo to our lives. Their disruption (e.g., by shiftwork) therefore carries a severe cost in health. The suprachiasmatic nucleus (SCN) is the principal brain clock of mammals, its time keeping pivoting around a delayed negative feedback loop of gene and protein expression. By using “translational switching” as a means to reversibly control the expression of the negative feedback regulator Cryptochrome 1 (CRY1) in SCN organotypic slices, we show that acute changes in the level of CRY1 define circadian time. We thereby bridge theoretical and biochemical perspectives of the SCN clockwork. The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal clock driving circadian rhythms of physiology and behavior that adapt mammals to environmental cycles. Disruption of SCN-dependent rhythms compromises health, and so understanding SCN time keeping will inform management of diseases associated with modern lifestyles. SCN time keeping is a self-sustaining transcriptional/translational delayed feedback loop (TTFL), whereby negative regulators inhibit their own transcription. Formally, the SCN clock is viewed as a limit-cycle oscillator, the simplest being a trajectory of successive phases that progresses through two-dimensional space defined by two state variables mapped along their respective axes. The TTFL motif is readily compatible with limit-cycle models, and in Neurospora and Drosophila the negative regulators Frequency (FRQ) and Period (Per) have been identified as state variables of their respective TTFLs. The identity of state variables of the SCN oscillator is, however, less clear. Experimental identification of state variables requires reversible and temporally specific control over their abundance. Translational switching (ts) provides this, the expression of a protein of interest relying on the provision of a noncanonical amino acid. We show that the negative regulator Cryptochrome 1 (CRY1) fulfills criteria defining a state variable: ts-CRY1 dose-dependently and reversibly suppresses the baseline, amplitude, and period of SCN rhythms, and its acute withdrawal releases the TTFL to oscillate from a defined phase. Its effect also depends on its temporal pattern of expression, although constitutive ts-CRY1 sustained (albeit less stable) oscillations. We conclude that CRY1 has properties of a state variable, but may operate among several state variables within a multidimensional limit cycle.
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影响因子：
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通讯作者：
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