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Changes in oscillatory dynamics in the cell cycle of early Xenopus laevis embryos.

Tsai TY, Theriot JA, Ferrell JE - PLoS Biol. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, United States of America ; Department of Biochemistry, Stanford University School of Medicine, Stanford, California, United States of America ; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT
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.

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Modeled robustness and tunability from negative-feedback-only versus positive-plus-negative feedback.(A) Robustness score of the oscillator assuming various degrees of ultrasensitivity in the negative feedback loop (n  =  4, 9, or 36; see Text S2), and various values of r. (B, C) Tunability. Each of the model’s parameters was varied up and down by 32-fold, starting with a value of r that made the model run like a negative-feedback-only oscillator (r  =  1/32, panel B) or a positive-plus-negative feedback oscillator (r  =  1/2, panel C). The bars show the maximum increases (B) and decreases (C) in period that resulted. The green bars correspond to parameters related to the positive feedback, the red bars to negative feedback, and the yellow bars represent cyclin synthesis.
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pbio-1001788-g006: Modeled robustness and tunability from negative-feedback-only versus positive-plus-negative feedback.(A) Robustness score of the oscillator assuming various degrees of ultrasensitivity in the negative feedback loop (n  =  4, 9, or 36; see Text S2), and various values of r. (B, C) Tunability. Each of the model’s parameters was varied up and down by 32-fold, starting with a value of r that made the model run like a negative-feedback-only oscillator (r  =  1/32, panel B) or a positive-plus-negative feedback oscillator (r  =  1/2, panel C). The bars show the maximum increases (B) and decreases (C) in period that resulted. The green bars correspond to parameters related to the positive feedback, the red bars to negative feedback, and the yellow bars represent cyclin synthesis.

Mentions: Previous modeling studies and experimental studies have shown that a bistable trigger can contribute robustness to the generation of oscillations, and it has been argued that this might be one reason why positive-plus-negative feedback designs are so common in biological oscillators [23],[24],[54],[55]. However, the cell cycle appears to proceed reliably and with a very regular period in Xenopus embryos during cycles 2–12, where the bistable trigger is essentially inoperative (Figures 2–4). We therefore set out to determine whether the highly ultrasensitive activation of APC/CCdc20, which we now know to be present in the embryonic cell cycle [50], might obviate the need for a bistable trigger. As a measure of robustness, we randomly varied the model’s parameters and scored the percentage of parameter sets that yielded oscillations (Text S2). As shown in the inset to Figure 6A, when relatively low levels of ultrasensitivity were assumed for the negative feedback loop, positive feedback contributed to the robustness of oscillations. However, if we assumed realistically high levels of ultrasensitivity in the negative feedback loop, the oscillations were extremely robust irrespective of whether we assumed a high or low value for r (Figure 6A). This finding implies that even though a bistable trigger can promote oscillations, high ultrasensitivity in the negative feedback loop may make a bistable trigger inessential. Thus, both the strong and weak positive feedback versions of the model can generate robust oscillations.


Changes in oscillatory dynamics in the cell cycle of early Xenopus laevis embryos.

Tsai TY, Theriot JA, Ferrell JE - PLoS Biol. (2014)

Modeled robustness and tunability from negative-feedback-only versus positive-plus-negative feedback.(A) Robustness score of the oscillator assuming various degrees of ultrasensitivity in the negative feedback loop (n  =  4, 9, or 36; see Text S2), and various values of r. (B, C) Tunability. Each of the model’s parameters was varied up and down by 32-fold, starting with a value of r that made the model run like a negative-feedback-only oscillator (r  =  1/32, panel B) or a positive-plus-negative feedback oscillator (r  =  1/2, panel C). The bars show the maximum increases (B) and decreases (C) in period that resulted. The green bars correspond to parameters related to the positive feedback, the red bars to negative feedback, and the yellow bars represent cyclin synthesis.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3921120&req=5

pbio-1001788-g006: Modeled robustness and tunability from negative-feedback-only versus positive-plus-negative feedback.(A) Robustness score of the oscillator assuming various degrees of ultrasensitivity in the negative feedback loop (n  =  4, 9, or 36; see Text S2), and various values of r. (B, C) Tunability. Each of the model’s parameters was varied up and down by 32-fold, starting with a value of r that made the model run like a negative-feedback-only oscillator (r  =  1/32, panel B) or a positive-plus-negative feedback oscillator (r  =  1/2, panel C). The bars show the maximum increases (B) and decreases (C) in period that resulted. The green bars correspond to parameters related to the positive feedback, the red bars to negative feedback, and the yellow bars represent cyclin synthesis.
Mentions: Previous modeling studies and experimental studies have shown that a bistable trigger can contribute robustness to the generation of oscillations, and it has been argued that this might be one reason why positive-plus-negative feedback designs are so common in biological oscillators [23],[24],[54],[55]. However, the cell cycle appears to proceed reliably and with a very regular period in Xenopus embryos during cycles 2–12, where the bistable trigger is essentially inoperative (Figures 2–4). We therefore set out to determine whether the highly ultrasensitive activation of APC/CCdc20, which we now know to be present in the embryonic cell cycle [50], might obviate the need for a bistable trigger. As a measure of robustness, we randomly varied the model’s parameters and scored the percentage of parameter sets that yielded oscillations (Text S2). As shown in the inset to Figure 6A, when relatively low levels of ultrasensitivity were assumed for the negative feedback loop, positive feedback contributed to the robustness of oscillations. However, if we assumed realistically high levels of ultrasensitivity in the negative feedback loop, the oscillations were extremely robust irrespective of whether we assumed a high or low value for r (Figure 6A). This finding implies that even though a bistable trigger can promote oscillations, high ultrasensitivity in the negative feedback loop may make a bistable trigger inessential. Thus, both the strong and weak positive feedback versions of the model can generate robust oscillations.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, United States of America ; Department of Biochemistry, Stanford University School of Medicine, Stanford, California, United States of America ; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT
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.

Show MeSH