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PERIOD-TIMELESS interval timer may require an additional feedback loop.

Kuczenski RS, Hong KC, García-Ojalvo J, Lee KH - PLoS Comput. Biol. (2007)

Bottom Line: In this study we present a detailed, mechanism-based mathematical framework of Drosophila circadian rhythms.This framework facilitates a more systematic approach to understanding circadian rhythms using a comprehensive representation of the network underlying this phenomenon.The possible mechanisms underlying the cytoplasmic "interval timer" created by PERIOD-TIMELESS association are investigated, suggesting a novel positive feedback regulatory structure.

View Article: PubMed Central - PubMed

Affiliation: School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, United States of America.

ABSTRACT
In this study we present a detailed, mechanism-based mathematical framework of Drosophila circadian rhythms. This framework facilitates a more systematic approach to understanding circadian rhythms using a comprehensive representation of the network underlying this phenomenon. The possible mechanisms underlying the cytoplasmic "interval timer" created by PERIOD-TIMELESS association are investigated, suggesting a novel positive feedback regulatory structure. Incorporation of this additional feedback into a full circadian model produced results that are consistent with previous experimental observations of wild-type protein profiles and numerous mutant phenotypes.

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A Detailed Framework of Circadian Rhythms in Drosophila
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pcbi-0030154-g001: A Detailed Framework of Circadian Rhythms in Drosophila

Mentions: Circadian rhythmicity is the product of a robust [1], free-running, temperature-compensated [2], and adaptable [3,4] biological clock found in diverse organisms ranging from bacteria to humans. The model organism Drosophila is commonly used to study this phenomenon due to the relative ease of experimentation and the similarities to the mammalian circadian clock (reviewed in [5,6]). The Drosophila circadian clock is composed of two interlocking feedback loops, shown in Figure 1. The first loop is composed of the negative feedback of period (per) and timeless (tim), shown in red, which down-regulate their own expression by inhibiting the CLOCK–CYCLE (CLK–CYC) transcription factor. DOUBLE-TIME (DBT) binds to and phosphorylates PER, which dimerizes with TIM before localizing to the nucleus via an uncharacterized mechanism. Circadian rhythms are entrained by light through an increased degradation of TIM protein, shown in yellow. In the second loop, shown in blue, the expression of clk is regulated by vrille (vri) and PAR domain protein 1 isoform ɛ (pdp). Both vri and pdp expression are activated by CLK–CYC. VRI represses the expression of clk, creating a negative feedback loop, whereas PDP creates a positive feedback loop through activating clk expression. Incorporating detail on interlocked feedback loops, recently shown to increase the stability and robustness of oscillations [7,8], may be important to accurately capture the network behavior.


PERIOD-TIMELESS interval timer may require an additional feedback loop.

Kuczenski RS, Hong KC, García-Ojalvo J, Lee KH - PLoS Comput. Biol. (2007)

A Detailed Framework of Circadian Rhythms in Drosophila
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1937016&req=5

pcbi-0030154-g001: A Detailed Framework of Circadian Rhythms in Drosophila
Mentions: Circadian rhythmicity is the product of a robust [1], free-running, temperature-compensated [2], and adaptable [3,4] biological clock found in diverse organisms ranging from bacteria to humans. The model organism Drosophila is commonly used to study this phenomenon due to the relative ease of experimentation and the similarities to the mammalian circadian clock (reviewed in [5,6]). The Drosophila circadian clock is composed of two interlocking feedback loops, shown in Figure 1. The first loop is composed of the negative feedback of period (per) and timeless (tim), shown in red, which down-regulate their own expression by inhibiting the CLOCK–CYCLE (CLK–CYC) transcription factor. DOUBLE-TIME (DBT) binds to and phosphorylates PER, which dimerizes with TIM before localizing to the nucleus via an uncharacterized mechanism. Circadian rhythms are entrained by light through an increased degradation of TIM protein, shown in yellow. In the second loop, shown in blue, the expression of clk is regulated by vrille (vri) and PAR domain protein 1 isoform ɛ (pdp). Both vri and pdp expression are activated by CLK–CYC. VRI represses the expression of clk, creating a negative feedback loop, whereas PDP creates a positive feedback loop through activating clk expression. Incorporating detail on interlocked feedback loops, recently shown to increase the stability and robustness of oscillations [7,8], may be important to accurately capture the network behavior.

Bottom Line: In this study we present a detailed, mechanism-based mathematical framework of Drosophila circadian rhythms.This framework facilitates a more systematic approach to understanding circadian rhythms using a comprehensive representation of the network underlying this phenomenon.The possible mechanisms underlying the cytoplasmic "interval timer" created by PERIOD-TIMELESS association are investigated, suggesting a novel positive feedback regulatory structure.

View Article: PubMed Central - PubMed

Affiliation: School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, United States of America.

ABSTRACT
In this study we present a detailed, mechanism-based mathematical framework of Drosophila circadian rhythms. This framework facilitates a more systematic approach to understanding circadian rhythms using a comprehensive representation of the network underlying this phenomenon. The possible mechanisms underlying the cytoplasmic "interval timer" created by PERIOD-TIMELESS association are investigated, suggesting a novel positive feedback regulatory structure. Incorporation of this additional feedback into a full circadian model produced results that are consistent with previous experimental observations of wild-type protein profiles and numerous mutant phenotypes.

Show MeSH