What makes the circadian clock tick: genes that keep time?

Intense activity in the field of circadian rhythms has led in recent years to a basic understanding of how an endogenous clock is generated. Oscillating products of the period (per) and timeless (tim) genes, which feed back to regulate their own synthesis, and transcription factors, which activate these genes, combine to generate a molecular loop that apparently drives behavioral and physiological rhythms. The best-characterized component of this system is the per gene, with considerable effort directed towards identifying the mechanisms that regulate cyclic expression of RNA and protein. Since the cycling of PER protein is controlled largely by post-transcriptional mechanisms, the relative importance of RNA versus protein cycling has been addressed in several studies that are discussed in this chapter. However, it now is clear that regulation of per cannot be dissociated from that of tim, since they are co-dependent components. The overt behavioral phenotype likely depends upon the effect that any perturbation has on both components, rather than on either alone. Major features of the feedback loop appear to be conserved, from fruit flies to mammals. One difference between the two systems is the manner in which the "molecular clock" responds to light. In flies, levels of TIM protein are reduced in response to light, while in mammals, per RNA is induced. The pathway that conducts light to the clock is poorly understood but there is increasing evidence in support of a dedicated pathway for circadian photoreception, as opposed to the sole use of the visual transduction system.