The Circadian Clocks of Mice and Men

and the resulting dimer can bind to E box elements and activate transcription (references in Bunger et al., 2000; Maemura et al., 2000). Moreover, Bmal2 is expressed The molecular dissection of the mammalian circadian in the SCN. The discovery of Bmal2 raised questions clock continues to yield exciting and important discover-concerning the importance of Bmal1 in the SCN clock-ies. Here we review the recent progress in the field, work. For example, are Bmal1 and Bmal2 functionally highlighting work on the central clock mechanism itself, redundant, or is only one BMAL the " true " partner for the photopigments involved in the entrainment of the CLOCK? central clock by light, and the signals that entrain periph-All doubts of Bmal1's importance in the SCN clock eral oscillators. Of special interest is a recent discovery were laid to rest with the recent characterization of promising further progress in circadian biology using Bmal1 knockout mice by Bradfield and colleagues human genetics to complement laboratory animal re-(Bunger et al., 2000). These mutant mice become ar-search (Toh et al., 2001). A goal of mammalian clock rhythmic immediately upon placement in constant dark-research is to provide a full understanding of the intricate ness, indicating that the SCN clockwork is not functional workings of our circadian clock. This knowledge will without Bmal1. Moreover, mPer1 and mPer2 RNA levels help identify human clock disorders and ultimately lead are constitutively low in the SCN of the mutant mice, to more effective ways to manipulate circadian timing indicating that BMAL1 is required to activate transcrip-for coping with shift work and for treating jet lag and tion of clock genes. circadian-based sleep and neuropsychiatric disorders. These findings mesh beautifully with data from Clock/ Circadian rhythms, those biological oscillations with Clock mutant mice (Gekakis et al., 1998). The mutant a period of about 24 hr, are virtually ubiquitous, oc-CLOCK protein can still dimerize with BMAL1 and bind curring in cyanobacteria, protists, fungi, plants, and ani-DNA but is missing part of its transactivation domain. mals. In mammals, the " master clock " controlling circa-The mutant protein thereby acts in a dominant-negative dian rhythms resides in the suprachiasmatic nuclei fashion, preventing normal CLOCK from activating tran-(SCN) of the hypothalamus (reviewed by Weaver, 1998). scription of its target genes. Consistent with this model, Photic entrainment is the process by which the SCN are mPer and mCry RNA rhythms are blunted in Clock/Clock synchronized to a 24 …