Systemic integrity is largely dependent on the coherent function of the sub-systems composing the network. Their circadian rhythmicity is further related to the integrity of humoral and neuronal entraining signals, further underscoring the need of a system-level approach in order understand the underlying properties and design principles.
Quantitative mathematical models have been applied to gain mechanistic insights into clock gene network function [4-9] (Table 1). Among them, Becker-Weinmann et al. using a reduced model to simulate clock genes network, denoted that the negative feedback loop among Per and Cry genes is critically important for the maintenance of clock gene oscillations. They showed that even if the positive feedback loop among Bmal, Ror and Rev-erbα genes is substituted by a constantly expressed activator, oscillations can still occur. These modeling results were supported by the experimental evidence showing that Rev-erbα -/- mutant mice have rhythmic behavior even though their positive feedback mechanism is not functional. More