Genetic and molecular analysis of the central and peripheral circadian clockwork of mice.

A hierarchy of interacting, tissue-based clocks controls circadian physiology and behavior in mammals. Preeminent are the suprachiasmatic nuclei (SCN): central hypothalamic pacemakers synchronized to solar time via retinal afferents and in turn responsible for internal synchronization of other clocks present in major organ systems. The SCN and peripheral clocks share essentially the same cellular timing mechanism. This consists of autoregulatory transcriptional/posttranslational feedback loops in which the Period (Per) and Cryptochrome (Cry) "clock" genes are negatively regulated by their protein products. Here, we review recent studies directed at understanding the molecular and cellular bases to the mammalian clock. At the cellular level, we demonstrate the role of F-box protein Fbxl3 (characterized by the afterhours mutation) in directing the proteasomal degradation of Cry and thereby controlling negative feedback and circadian period of the molecular loops. Within SCN neural circuitry, we describe how neuropeptidergic signaling by VIP synchronizes and sustains the cellular clocks. At the hypothalamic level, signaling via a different SCN neuropeptide, prokineticin, is not required for pacemaking but is necessary for control of circadian behavior. Finally, we consider how metabolic pathways are coordinated in time, focusing on liver function and the role of glucocorticoid signals in driving the circadian transcriptome and proteome.