Changes in oscillatory dynamics in the cell cycle of early Xenopus laevis embryos.
Changes in oscillatory dynamics in the cell cycle of early Xenopus laevis embryos.
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DOI：
10.1371/journal.pbio.1001788
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发表时间：
2014-02
期刊：
影响因子：
9.8
通讯作者：
Ferrell JE Jr
中科院分区：
文献类型：
--
作者：
Tsai TY;Theriot JA;Ferrell JE Jr
非洲爪蟾胚胎细胞周期的一项定量研究揭示了在最初的几个周期中，两种类型的振荡器动力学之间的过渡，以满足两种不同的发育要求，从而提高胚胎的生存能力。在非洲爪蟾胚胎的早期发育过程中，第一个有丝分裂细胞周期较长（约85分钟），随后的11个周期较短（约30分钟）且呈时钟状。在这里，我们解决了Cdk1细胞周期振荡器如何在这两种操作模式之间变化的问题。我们发现这种变化可归因于Wee1/Myt1和Cdc25之间平衡的改变。平衡的变化将一个像正负反馈振荡器一样的电路转换为一个像负反馈振荡器一样的电路，具有Cdk1激活的尖峰，具有更短的周期和平稳变化的Cdk1活性。用Wee1A/Myt1抑制剂PD0166285处理胚胎，缩短第一周期，导致胚胎活力显著降低，用低剂量环己亚胺恢复抑制剂处理的胚胎的第一周期长度部分恢复了活力。用实验参数化数学模型计算表明，Wee1/Cdc25比值的适度变化可以解释细胞周期中观察到的质变。在第一个周期的高比率允许周期是长和可调的，并在随后的周期中降低比率允许振荡器以最大速度运行。因此，胚胎在早期发育过程中，为了满足两种不同的发育需求，重新布线了反馈调节。早期胚胎细胞周期开始细胞分裂，标志着生物体生命的开始。在不同的门中，这些周期具有一个特征的时间模式，第一个周期较长，随后的周期较短，导致细胞数量迅速增加。本文以非洲爪蟾胚胎为研究对象，探讨了这一时间性转变的机制和意义。在紫毛猴胚胎中，细胞周期是由周期蛋白B-Cdk1复合物活性的振荡驱动的，该复合物通过蛋白磷酸化调节细胞周期进程。我们量化了前几个胚胎细胞周期中关键调控因子的振荡动力学，并建立了振荡的实验参数化数学模型。我们发现，激活cdk1的磷酸酶Cdc25和抑制cdk1的激酶Wee1和Myt1之间平衡的变化对这种转变至关重要。调节这种平衡转换周期蛋白B-Cdk1振荡器从产生尖刺振荡与延迟激活，平滑变化的振荡与较短的周期。此外，我们发现第一个胚胎细胞周期足够长是至关重要的，因为用药物缩短它会大大降低胚胎的生存能力。我们的研究显示了狐猴胚胎如何调节其细胞周期振荡器动力学以满足两个发育要求：足够长的第一个细胞周期和随后周期的快速进展。
A quantitative study of the Xenopus laevis embryonic cell cycle reveals a transition in the first few cycles between two types of oscillator dynamics to meet two different developmental requirements that increase embryo viability. During the early development of Xenopus laevis embryos, the first mitotic cell cycle is long (∼85 min) and the subsequent 11 cycles are short (∼30 min) and clock-like. Here we address the question of how the Cdk1 cell cycle oscillator changes between these two modes of operation. We found that the change can be attributed to an alteration in the balance between Wee1/Myt1 and Cdc25. The change in balance converts a circuit that acts like a positive-plus-negative feedback oscillator, with spikes of Cdk1 activation, to one that acts like a negative-feedback-only oscillator, with a shorter period and smoothly varying Cdk1 activity. Shortening the first cycle, by treating embryos with the Wee1A/Myt1 inhibitor PD0166285, resulted in a dramatic reduction in embryo viability, and restoring the length of the first cycle in inhibitor-treated embryos with low doses of cycloheximide partially rescued viability. Computations with an experimentally parameterized mathematical model show that modest changes in the Wee1/Cdc25 ratio can account for the observed qualitative changes in the cell cycle. The high ratio in the first cycle allows the period to be long and tunable, and decreasing the ratio in the subsequent cycles allows the oscillator to run at a maximal speed. Thus, the embryo rewires its feedback regulation to meet two different developmental requirements during early development. The early embryonic cell cycles, which initiate cell division, mark the beginning of the life of an organism. Across different phyla, these cycles have a characteristic temporal pattern, with the first cycle being long and the subsequent cycles shorter, leading to rapid increase in cell numbers. Here we have made use of the Xenopus laevis embryos to study the mechanism and significance of this temporal transition. In X. laevis embryos, the cell cycles are driven by oscillations in the activity of the cyclin B–Cdk1 complex, which regulates cell cycle progression by protein phosphorylation. We quantified the oscillatory dynamics of key regulators in the first few embryonic cell cycles, and developed an experimentally parameterized mathematical model of the oscillations. We found that a change in the balance between the Cdk1-activating phosphatase Cdc25 and the Cdk1-inhibiting kinases Wee1 and Myt1 is critical for this transition. Tuning this balance converts the cyclin B–Cdk1 oscillator from generating spiky oscillations with delayed activation, to smooth-varying oscillations with a shorter period. Moreover, we found that it is crucial for the first embryonic cell cycle to be sufficiently long, as shortening it with drugs dramatically decreases embryo viability. Our work shows how X. laevis embryos modulate their cell cycle oscillator dynamics to meet two developmental requirements: a sufficiently long first cell cycle and rapid progression of the subsequent cycles.
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影响因子：
6.7
作者：
Chen AA;Tan L;Suraj V;Reijo Pera R;Shen S
通讯作者：
Shen S
影响因子：
16
作者：
Ferrell JE Jr
通讯作者：
Ferrell JE Jr
DOI：
10.1098/rspb.1995.0153
发表时间：
1995-09-22
影响因子：
4.7
作者：
GOLDBETER, A
通讯作者：
GOLDBETER, A
DOI：
10.1073/pnas.0900751106
发表时间：
2009-03-24
影响因子：
11.1
作者：
Lee, Gwanghee;White, Lynn S.;Piwnica-Worms, Helen
通讯作者：
Piwnica-Worms, Helen
DOI：
10.1073/pnas.77.1.462
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
HARA, K;TYDEMAN, P;KIRSCHNER, M
通讯作者：
KIRSCHNER, M