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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.

Show MeSH
The embryonic cell cycle oscillator consists of interlinked positive-and-negative feedback loops.Cyclin B–Cdk1 inhibits its inhibitory kinases Wee1 and Myt1, forming a double negative feedback loop, which in many respects is equivalent to a positive feedback loop. Cyclin B–Cdk1 activates its activating phosphatase Cdc25, forming a positive feedback loop. Active cyclin B–Cdk1 also activates the E3 ubiquitin ligase APC/CCdc20, which targets cyclin B for degradation. The Cdk1–APC/CCdc20 circuit is therefore a negative feedback loop.
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pbio-1001788-g001: The embryonic cell cycle oscillator consists of interlinked positive-and-negative feedback loops.Cyclin B–Cdk1 inhibits its inhibitory kinases Wee1 and Myt1, forming a double negative feedback loop, which in many respects is equivalent to a positive feedback loop. Cyclin B–Cdk1 activates its activating phosphatase Cdc25, forming a positive feedback loop. Active cyclin B–Cdk1 also activates the E3 ubiquitin ligase APC/CCdc20, which targets cyclin B for degradation. The Cdk1–APC/CCdc20 circuit is therefore a negative feedback loop.

Mentions: The Xenopus embryonic cell cycle is autonomous in character. Cell cycle oscillations persist in the absence of transcriptional activity, DNA replication, and normal microtubule function [6],[7]. The biochemical regulatory circuit that generates these oscillations is centered on the cyclin B-cyclin–dependent kinase 1 (Cdk1) complex, which is the master regulator of mitosis (Figure 1). Cyclin B–Cdk1 is active only when Cdk1 is in the correct phosphorylation state, with Thr 161 phosphorylated and Thr 14 and Tyr 15 dephosphorylated [8]. The kinases Wee1 and Myt1 phosphorylate Thr 14 and Tyr 15 and thereby inactivate Cdk1 [9]–[11]. Both Wee1 and Myt1 are inactivated by Cdk1, forming a double-negative feedback loop [12]–[14], which is similar in many respects to a positive feedback loop. Two phosphatases, Cdc25A and Cdc25C, dephosphorylate Tyr 15 and activate Cdk1 [15]–[18]. In addition, Cdc25C is activated by Cdk1, forming a positive feedback loop [19],[20]. The positive and double-negative feedback loops constitute a bistable trigger [21],[22], and this trigger has been shown through both computational studies [23],[24] and experimental studies [24] to be important for the robustness of the oscillator. Once the bistable switch has been flipped to the Cdk1-on state, Cdk1 activates the anaphase-promoting complex or cyclosome (APC/C), which in Xenopus embryos utilizes only the Cdc20 co-activator protein [25]. APC/CCdc20 targets cyclin for degradation by the proteosome. The Cdk1–APC/CCdc20 system constitutes a negative feedback loop, and it is essential for cell cycle oscillations [26].


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

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

The embryonic cell cycle oscillator consists of interlinked positive-and-negative feedback loops.Cyclin B–Cdk1 inhibits its inhibitory kinases Wee1 and Myt1, forming a double negative feedback loop, which in many respects is equivalent to a positive feedback loop. Cyclin B–Cdk1 activates its activating phosphatase Cdc25, forming a positive feedback loop. Active cyclin B–Cdk1 also activates the E3 ubiquitin ligase APC/CCdc20, which targets cyclin B for degradation. The Cdk1–APC/CCdc20 circuit is therefore a negative feedback loop.
© Copyright Policy
Related In: Results  -  Collection

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

pbio-1001788-g001: The embryonic cell cycle oscillator consists of interlinked positive-and-negative feedback loops.Cyclin B–Cdk1 inhibits its inhibitory kinases Wee1 and Myt1, forming a double negative feedback loop, which in many respects is equivalent to a positive feedback loop. Cyclin B–Cdk1 activates its activating phosphatase Cdc25, forming a positive feedback loop. Active cyclin B–Cdk1 also activates the E3 ubiquitin ligase APC/CCdc20, which targets cyclin B for degradation. The Cdk1–APC/CCdc20 circuit is therefore a negative feedback loop.
Mentions: The Xenopus embryonic cell cycle is autonomous in character. Cell cycle oscillations persist in the absence of transcriptional activity, DNA replication, and normal microtubule function [6],[7]. The biochemical regulatory circuit that generates these oscillations is centered on the cyclin B-cyclin–dependent kinase 1 (Cdk1) complex, which is the master regulator of mitosis (Figure 1). Cyclin B–Cdk1 is active only when Cdk1 is in the correct phosphorylation state, with Thr 161 phosphorylated and Thr 14 and Tyr 15 dephosphorylated [8]. The kinases Wee1 and Myt1 phosphorylate Thr 14 and Tyr 15 and thereby inactivate Cdk1 [9]–[11]. Both Wee1 and Myt1 are inactivated by Cdk1, forming a double-negative feedback loop [12]–[14], which is similar in many respects to a positive feedback loop. Two phosphatases, Cdc25A and Cdc25C, dephosphorylate Tyr 15 and activate Cdk1 [15]–[18]. In addition, Cdc25C is activated by Cdk1, forming a positive feedback loop [19],[20]. The positive and double-negative feedback loops constitute a bistable trigger [21],[22], and this trigger has been shown through both computational studies [23],[24] and experimental studies [24] to be important for the robustness of the oscillator. Once the bistable switch has been flipped to the Cdk1-on state, Cdk1 activates the anaphase-promoting complex or cyclosome (APC/C), which in Xenopus embryos utilizes only the Cdc20 co-activator protein [25]. APC/CCdc20 targets cyclin for degradation by the proteosome. The Cdk1–APC/CCdc20 system constitutes a negative feedback loop, and it is essential for cell cycle oscillations [26].

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