Abstract
Circadian clock genes serve as the molecular basis for animals’ ~24-h internal timekeeping. Clock gene expression inside and outside of the mammalian brain’s circadian pacemaker (i.e. the SCN) integrates temporal information into a wealth of physiological processes. Ample data suggests that in addition to canonical cellular timekeeping functions, clock proteins also interact with proteins involved in cellular processes not related to timekeeping, including protein regulation and the interaction with other signaling mechanisms not directly linked to the regulation of circadian rhythms. Indeed, recent data suggests that clock genes outside the SCN are involved in fundamental brain processes such as sleep/wakefulness, stress and memory. The role of clock genes in these brain processes are complex and divers, influencing many molecular pathways and phenotypes. In this review, we will discuss recent work on the involvement of clock genes in sleep, stress, and memory. Moreover, we raise the controversial possibility that these functions may be under certain circumstances independent of their circadian timekeeping function.
Highlights
circadian locomotor output cycles kaput (Clock) genes serve as the basis of an intracellular timekeeping system, present throughout the body, which generates approximately 24-hour rhythms in physiology and behavior
Removal of the Suprachiasmatic nucleus (SCN) leads to arrhythmicity of some local clocks like in the hippocampus [13,92,93], and is not accompanied by alter ations in homeostatic sleep processes [52]. This latter observation sug gests that alterations in homeostatic sleep response may not be caused by local clock distortions, but might rather be a consequence of clock gene interactions with homeostatic sleep processes irrespective from their circadian oscillations. These findings show that clock genes may regulate the circadian timing aspects of sleep which initiated by clock genes in the SCN
These findings suggest that acute stress responses may selectively alter Per1 expression, with compara tively modest and brain area-specific effects on other clock genes
Summary
Clock genes serve as the basis of an intracellular timekeeping system, present throughout the body, which generates approximately 24-hour rhythms in physiology and behavior. BMAL1 and CLOCK (or NPAS2) proteins are basic helix-loop-helix (bHLH)- Per-Arnt-Sim (PAS) transcription factors [35], which form heterodimer complexes through their PAS domains. As heterodimer complexes they interact with promoter region E-box sites via their bHLH domain, initiating the transcription of Per, Per, Cry, and Cry genes [30,79]. Besides clock protein interactions with one another, some clock proteins interact with a broad array of other proteins [46]; these interactions may modulate cellular processes including protein tran scription, stabilization, and trafficking This interaction with proteins not involved in circadian timekeeping has been proposed as a mecha nism for integrating time-of-day information into basic cellular pro cesses [3,70]. We provide a perspective on additional non-clock related function of clock genes, and how they could be studied in future experiments
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