Genetics of the mammalian circadian system: Photic entrainment, circadian pacemaker mechanisms, and posttranslational regulation

During the past four years, significant progress has been made in identifying the molecular components of the mammalian circadian clock system. An autoregulatory transcriptional feedback loop similar to that described in Drosophila appears to form the core circadian rhythm generating mechanism in mammals. Two basic helix-loop-helix (bHLH) PAS (PER-ARNT-SIM) transcription factors, CLOCK and BMAL1, form the positive elements of the system and drive transcription of three Period and two Cryptochrome genes. The protein products of these genes are components of a negative feedback complex that inhibits CLOCK and BMAL1 to close the circadian loop. In this review, we focus on three aspects of the circadian story in mammals: the genetics of the photic entrainment pathway; the molecular components of the circadian pacemaker in the hypothalamic suprachiasmatic nucleus; and the role of posttranslational regulation of circadian elements. A molecular description of the mammalian circadian system has revealed that circadian oscillations may be a fundamental property of many cells in the body and that a circadian hierarchy underlies the temporal organization of animals.