The Per2 Negative Feedback Loop Sets the Period in the Mammalian Circadian Clock Mechanism

TitleThe Per2 Negative Feedback Loop Sets the Period in the Mammalian Circadian Clock Mechanism
Publication TypeJournal Article
Year of Publication2007
AuthorsA. Wilkins K, Barton PI, Tidor B
JournalPLoS Comput Biol
Volume3
Paginatione242
Date Published12
Abstract

Processes that repeat in time, such as the cell cycle, the circadian rhythm, and seasonal variations, are prevalent in biology. Mathematical models can represent our knowledge of the underlying mechanisms, and numerical methods can then facilitate analysis, which forms the foundation for a more integrated understanding as well as for design and intervention. Here, the intracellular molecular network responsible for the mammalian circadian clock system was studied. A new formulation of detailed sensitivity analysis is introduced and applied to elucidate the influence of individual rate processes, represented through their parameters, on network functional characteristics. One of four negative feedback loops in the model, the {Per2} loop, was uniquely identified as most responsible for setting the period of oscillation; none of the other feedback loops were found to play as substantial a role. The analysis further suggested that the activity of the kinases {CK1$δ$} and {CK1$\varepsilon$} were well placed within the network such that they could be instrumental in implementing short-term adjustments to the period in the circadian clock system. The numerical results reported here are supported by previously published experimental data.

URLhttp://dx.plos.org/10.1371%2Fjournal.pcbi.0030242
DOI10.1371/journal.pcbi.0030242