Nature Reviews Molecular Cell Biology 1, 59-67 (2000)
MULTILEVEL REGULATION OF THE CIRCADIAN CLOCK
Nicolas Cermakian & Paolo Sassone-Corsi biogs Executive summary
· Living organisms adapt to light-dark rhythmicity using a complex programme based on internal clocks.
· In mammals, the central clock structure is located within the suprachiasmatic nucleus (SCN) of the anterior hypothalamus.
· The clock can be considered as consisting of three overlapping components: the input pathways, the oscillator or pacemaker (which generates rhythmicity autonomously) and the output pathways.
· Input-gene products are thought to sense external stimuli and relay the message to the oscillator to reset or entrain it.
· Many pacemaker genes encode transcription factors or proteins that act on gene regulation, emphasizing the idea that the generation and modulation of rhythms relies mainly on transcriptional feedback loops and on activation and repression of gene expression (perhaps through chromatin remodelling).
· The circadian clock probably uses a number of inter- or intragenic loops organized in networks.
· Degradation of clock messenger RNAs and proteins is crucial to the control of oscillator periodicity. Entry of clock proteins into the nucleus is another checkpoint for circadian feedback loops.
· Peripheral clocks may be controlled or synchronized by the SCN through blood-borne signalling factors oscillating in a circadian fashion.
· Output gene-products, which include peptides and transcription factors, convey rhythmic information to downstream physiological systems.