The circadian clock of the fly: a neurogenetics journey through time.

Forty years ago, a mutagenesis screening in the fruit fly, Drosophila melanogaster, led to the discovery of period, the first gene to be involved in the endogenous 24-h rhythmicity of an organism. Since then circadian clocks have been identified in fungi, cyanobacteria, plants, and other animals. Although the molecular components are not conserved across the main divisions of life, it appears that in every organism, a common design, based upon a transcription-translation feedback loop (TTL), is in place to regulate endogenous 24 h cycles. The TTL model has informed chronobiology research for the majority of the past 30 years with spectacular results. However, new evidence and the rediscovery of old observations suggest that this model is coming to age. Here, we provide a comprehensive review of the current TTL model in Drosophila highlighting its accomplishments and its limitations. We conclude by offering our personal view on the organization and the evolution of circadian clocks.