Ueda, Hagiwara, Kitano, 2001

Model Status

This CellML model is known to run in both PCEnv and COR to replicate the published results. The units have been checked and they are consistent.

Model Structure

Many living organisms, from bacteria to plants, insects to mammals, display circadian rhythms. These are spontaneously sustained oscillations with a period close to 24 hours. Even in the absence of environmental cues, such as the light changes associated with day and night, organisms have been shown to retain their circadian behaviour, therefore suggesting that the rhythms are endogenous. Experiments with Drosophila (fruit fly), Neurospora (fungus), cyanobacteria, plants and mammals have improved our understanding of the molecular mechanisms underlying circadian rhythms. It seems that they rely on a negative feedback on gene expression. A number of genes involved in circadian rhythms have been identified. These include: Per (period), Tim (timeless), Cyc (cycle), Clk (clock), dbt (doubletime), and Cry (cryptochrome). Among these genes, per, tim and Clk are rhythmically expressed. per and tim mRNA levels peak in the evening, where as Clk mRNA levels peak late at night or early in the morning.

Analysis of per and tim oscillatory expression has revealed a negative feedback loop ( per-tim feedback loop in the figure below). Several mathematical models of this negative feedback loop have been developed, and model simulations have shown that a delayed negative feedback loop is sufficient to produce spontaneous oscillations. However, these models fail to take into account the Clk negative feedback loop. Based on experimental analyses of Clk expression, Ueda et al. have developed a different type of mathematical model which they call an interlocked feedback model (as opposed to a simple model). The interlocked feedback model is composed of two coupled negative feedback loops: a per-tim feedback loop which is activated by CLK-CYC and inhibited by PER-TIM, and a Clk feedback loop, which is inhibited by CLK-CYC and reactivated by PER-TIM.

The complete original paper reference is cited below:

Robust Oscillations within the Interlocked Feedback Model of Drosophila Circadian Rhythm, Hiroki R. Ueda, Masatoshi Hagiwara, and Hiroaki Kitano, 2001, Journal of Theoretical Biology , 210, 401-406. (A PDF version of the article is available on the Journal of Theoretical Biology website.) PubMed ID: 11403460

The interlocked feedback model of Drosophila circadian rhythm.