The genetic and molecular analysis of circadian timekeeping mechanisms has accelerated as …

• Abstract
• Minireview
• Circadian oscillator mechanisms
• Clock output pathways
• References
• Table 1
• Figure

Circadian rhythms are fluctuations in physiological and behavioral activities that occur over a period of about 24 hours. Although these rhythms parallel environmental cycles of light and dark, they are not simply a reaction to environmental fluctuations, but are generated by an endogenous timekeeping mechanism called the circadian clock. The ability of the clock to persist in the absence of environmental cues provides internal temporal organization so that rhythmic activities can occur at characteristic times during the circadian cycle. In addition, two other clock properties, entrainment (that is, setting the clock to local time with respect to environmental cycles) and temperature compensation (that is, the ability of the clock to run at the same rate at different temperatures) ensure synchrony with the environment. The importance of the circadian clock is underscored by its ubiquity; clocks are present in organisms ranging from prokaryotic and eukaryotic microbes to plants, insects and mammals.

The circadian clock has been conceptualized as a series of three components: an 'entrainment pathway' that transmits environmental (usually light) signals to the timekeeping apparatus; a timekeeping apparatus, or 'oscillator', which operates in the absence of environmental cues and is the core component of the circadian clock; and 'output pathways' that are activated at specific times of the circadian cycle by the circadian oscillator. This framework has enabled us to concentrate on the mechanisms that interconnect these components to form an effective timekeeping system. Naturally, a great deal of effort has been focused on identifying genes that encode pieces of the oscillator - also known as 'clock genes'. The increasing volume of genomic and expressed sequence tag (EST) sequences has rapidly increased the pace of clock gene discovery, particularly in mammals; and the abundance of newly identified clock genes has given rise to detailed models of the oscillator mechanism. In contrast, relatively little effort has been put into identifying genes within output pathways, even though these pathways provide the critical links to rhythmic physiology and behavior. New tools that are now available for expression screening should enable rapid advances in the identification of output genes.