Oscillating Per-Cision

Primer T he field of behavioral genetics began nearly four decades ago, when Seymour Benzer's laboratory set out to identify circadian rhythm mutants in Drosophila melanogaster. The first of these was called period, and both short and long period alleles were found [1]. It was not until some years later that the mutant gene was identified and exploration of the molecular basis of the circadian clock began in earnest [2,3]. Over the years, forward screens in Drosophila have led to identification of a number of loci that contribute to circadian rhythm function with different phenotypes, including short and long periods and total arrhythmia [4]. Detailed investigations at a genetic and molecular level began to define the cellular and molecular basis of circadian rhythmicity. In its most basic form, the circadian clock of the fruit fly consists of transcriptional activators that turn on expression of two circadian and oscillating genes (period and timeless), which are translated into proteins (PER and TIM) targeted for degradation by phosphorylation. Physical interactions between PER and TIM regulate their movement to the nucleus, where they directly interact with the transcriptional activators and suppress the expression of their own genes [5]. These findings also established the repressor role for PER and TIM in the transcriptional feedback loop. The temporal lag from the transcription of these autorepressors—their translation, nuclear accumulation, and negative feedback until their degradation—requires around 24 hours (circadian), and therefore sets the speed of the clock. An interlocked positive feedback loop has also been characterized. It is remarkable that such a simple, yet elegant model could be the basis of regulation for something as critical as synchronization of behavioral and physiological rhythms to the dramatic changes in light/dark and temperature on planet Earth. Forward and reverse genetic investigation in rodents revealed that most of the Drosophila clock genes have counterparts in mammalian systems, although some have multiple homologs [6]. Many studies in the last decade established a similar basic clock system for mammals [7]; comparison of the fly and mouse clock demonstrated many conserved features, but some differences have also emerged [8,9]. For example, the role of TIM appears to have been replaced by CRY in mammals. In addition to the genes and proteins that were identified as constituting the core molecular clock in living cells, interest in the post-translational modification of core clock proteins grew, in part, because some of the core clock genes in …