Glucocorticoids play a key role in circadian cell cycle rhythms.
Glucocorticoids play a key role in circadian cell cycle rhythms.
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DOI：
10.1371/journal.pbio.0050078
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发表时间：
2007-04
期刊：
影响因子：
9.8
通讯作者：
Foulkes NS
中科院分区：
文献类型：
--
作者：
Dickmeis T;Lahiri K;Nica G;Vallone D;Santoriello C;Neumann CJ;Hammerschmidt M;Foulkes NS
生物钟输出通路通过将生物钟的时间信息传递到各种生理系统中发挥着关键作用。细胞自主和系统机制都被认为是时钟输出;然而，这些机制之间的相对重要性和相互作用却知之甚少。细胞周期代表了昼夜节律计时系统的高度保守的调节靶点。在此之前，我们已经证明，在斑马鱼，生物钟有能力产生的细胞自主机制在体外的日常节奏的S期。在这里，通过研究一组斑马鱼突变体，我们揭示了垂体-肾上腺轴在整个动物中建立这些节律方面也起着至关重要的作用。垂体促肾上腺皮质激素细胞减少或完全缺失的突变体显示细胞增殖节律减弱，而生物钟基因的表达不受影响。我们发现，皮质激素缺乏症与皮质醇水平降低有关，暗示糖皮质激素是昼夜细胞周期节律所需的全身信号通路的组成部分。引人注目的是，高振幅节律可以通过将突变幼虫暴露于糖皮质激素激动剂的紧张浓度来拯救。我们的工作表明，细胞自主时钟机制不足以在整个动物水平上建立昼夜细胞周期节律。相反，它们与糖皮质激素是其重要组成部分的系统信号环境协同作用。为了保证正常生长和避免肿瘤形成，必须严格控制细胞分裂的时间。值得注意的是，从细菌到人类，细胞通常只在一天中的特定时间分裂，这表明内部生物钟的影响。大脑中的中央起搏器结构控制着行为和激素释放的昼夜节律。然而，生物钟也几乎在每一种细胞类型（所谓的“外围”时钟）中遇到，它们调节细胞生物学的日常变化，包括细胞分裂。迄今为止，人们对这两个时钟系统如何相互作用知之甚少。在这里，通过检查在激素生产缺陷的斑马鱼品系，我们发现，外周时钟需要类固醇激素皮质醇产生细胞增殖的日常节奏。有趣的是，在正常斑马鱼中观察到的皮质醇水平的每日变化并不是实现这种控制所必需的;用恒定水平的药物模拟皮质醇的作用来治疗皮质醇缺乏的品系恢复正常的细胞分裂节律。因此，似乎内部细胞计时器与激素信号合作来调节细胞分裂的时间。为了建立昼夜细胞周期节律，细胞自主时钟机制与糖皮质激素是其重要组成部分的系统信号环境协同作用。
Clock output pathways play a pivotal role by relaying timing information from the circadian clock to a diversity of physiological systems. Both cell-autonomous and systemic mechanisms have been implicated as clock outputs; however, the relative importance and interplay between these mechanisms are poorly understood. The cell cycle represents a highly conserved regulatory target of the circadian timing system. Previously, we have demonstrated that in zebrafish, the circadian clock has the capacity to generate daily rhythms of S phase by a cell-autonomous mechanism in vitro. Here, by studying a panel of zebrafish mutants, we reveal that the pituitary–adrenal axis also plays an essential role in establishing these rhythms in the whole animal. Mutants with a reduction or a complete absence of corticotrope pituitary cells show attenuated cell-proliferation rhythms, whereas expression of circadian clock genes is not affected. We show that the corticotrope deficiency is associated with reduced cortisol levels, implicating glucocorticoids as a component of a systemic signaling pathway required for circadian cell cycle rhythmicity. Strikingly, high-amplitude rhythms can be rescued by exposing mutant larvae to a tonic concentration of a glucocorticoid agonist. Our work suggests that cell-autonomous clock mechanisms are not sufficient to establish circadian cell cycle rhythms at the whole-animal level. Instead, they act in concert with a systemic signaling environment of which glucocorticoids are an essential part. To guarantee normal growth and to avoid tumor formation, the timing of cell division must be under strict control. Remarkably, cells, from bacteria to man, often divide only at certain times of day, suggesting the influence of internal biological clocks. A central pacemaker structure in the brain controls diurnal rhythms of behavior and hormone release. However, biological clocks are also encountered in almost every cell type (so-called “peripheral” clocks), in which they regulate daily changes in cell biology, including cell division. Very little is known to date about how the two clock systems interact. Here, by examining zebrafish strains with defects in hormone production, we find that peripheral clocks require the steroid hormone cortisol to generate daily rhythms of cell proliferation. Interestingly, the daily changes in cortisol levels observed in normal zebrafish are not required to achieve this control; treating the cortisol-deficient strains with constant levels of a drug that mimics the effects of cortisol restores normal cell-division rhythms. Thus, it appears that internal cell timers cooperate with hormonal signals to regulate the timing of cell division. To establish circadian cell cycle rhythms, cell-autonomous clock mechanisms act in concert with a systemic signaling environment of which glucocorticoids are an essential part.
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影响因子：
16
作者：
Gery, S;Komatsu, N;Koeffler, HP
通讯作者：
Koeffler, HP
影响因子：
3.6
作者：
Buckingham, JC;Solito, E;Morris, J
通讯作者：
Morris, J
影响因子：
56.9
作者：
Balsalobre, A;Brown, SA;Schibler, U
通讯作者：
Schibler, U
影响因子：
8.2
作者：
FOSTER, RG;GRACE, MS;GARCIAFERNANDEZ, JM
通讯作者：
GARCIAFERNANDEZ, JM
DOI：
10.1073/pnas.75.4.1882
发表时间：
1978-01-01
影响因子：
11.1
作者：
BAKER, JB;BARSH, GS;CUNNINGHAM, DD
通讯作者：
CUNNINGHAM, DD