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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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Inhibiting Cdk1 Y15 phosphorylation affects the duration of only the first cycle.(A) The period of the first three cycles from individual embryos treated with PD0166285. All periods are subtracted by the median value of the control of the same cycle to emphasize the differences. The three black lines correspond to 25, 50, and 75 percentile of the population. (B) Time courses of levels of cyclin B1, Cdk1 activity, and pY15–Cdk1 in control embryos and embryos treated with 50 µM PD0166285. (Inset) Higher magnification of pY15–Cdk1 traces from 2nd to 4th period.
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pbio-1001788-g003: Inhibiting Cdk1 Y15 phosphorylation affects the duration of only the first cycle.(A) The period of the first three cycles from individual embryos treated with PD0166285. All periods are subtracted by the median value of the control of the same cycle to emphasize the differences. The three black lines correspond to 25, 50, and 75 percentile of the population. (B) Time courses of levels of cyclin B1, Cdk1 activity, and pY15–Cdk1 in control embryos and embryos treated with 50 µM PD0166285. (Inset) Higher magnification of pY15–Cdk1 traces from 2nd to 4th period.

Mentions: Following fertilization there is a period of ∼30 min when cyclin B1 levels decrease and the first meiotic division is completed (Figure 2A,B). At this point the first mitotic cycle begins and cyclin B1 levels rise. During this rising phase, pY15–Cdk1 accumulates, indicating that some fraction of the cyclin–Cdk1 complexes are held inactive by Wee1A and Myt1. Assuming that cyclin B1 degradation is negligible in interphase, the cyclin B1 synthesis rate was estimated to be approximately 1.5 nM/min in all cycles (Figure 2A,B and Figure 3). By 60 min the cyclin B1 levels begin to fall, and ∼10 min before cleavage cyclin levels begin to increase again as the embryos exit their first mitosis.


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

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

Inhibiting Cdk1 Y15 phosphorylation affects the duration of only the first cycle.(A) The period of the first three cycles from individual embryos treated with PD0166285. All periods are subtracted by the median value of the control of the same cycle to emphasize the differences. The three black lines correspond to 25, 50, and 75 percentile of the population. (B) Time courses of levels of cyclin B1, Cdk1 activity, and pY15–Cdk1 in control embryos and embryos treated with 50 µM PD0166285. (Inset) Higher magnification of pY15–Cdk1 traces from 2nd to 4th period.
© Copyright Policy
Related In: Results  -  Collection

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

pbio-1001788-g003: Inhibiting Cdk1 Y15 phosphorylation affects the duration of only the first cycle.(A) The period of the first three cycles from individual embryos treated with PD0166285. All periods are subtracted by the median value of the control of the same cycle to emphasize the differences. The three black lines correspond to 25, 50, and 75 percentile of the population. (B) Time courses of levels of cyclin B1, Cdk1 activity, and pY15–Cdk1 in control embryos and embryos treated with 50 µM PD0166285. (Inset) Higher magnification of pY15–Cdk1 traces from 2nd to 4th period.
Mentions: Following fertilization there is a period of ∼30 min when cyclin B1 levels decrease and the first meiotic division is completed (Figure 2A,B). At this point the first mitotic cycle begins and cyclin B1 levels rise. During this rising phase, pY15–Cdk1 accumulates, indicating that some fraction of the cyclin–Cdk1 complexes are held inactive by Wee1A and Myt1. Assuming that cyclin B1 degradation is negligible in interphase, the cyclin B1 synthesis rate was estimated to be approximately 1.5 nM/min in all cycles (Figure 2A,B and Figure 3). By 60 min the cyclin B1 levels begin to fall, and ∼10 min before cleavage cyclin levels begin to increase again as the embryos exit their first mitosis.

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