The mammalian circadian timing system: from gene expression to physiology
- 1.6k Downloads
Many physiological processes in organisms from bacteria to man are rhythmic, and some of these are controlled by self-sustained oscillators that persist in the absence of external time cues. Circadian clocks are perhaps the best characterized biological oscillators and they exist in virtually all light-sensitive organisms. In mammals, they influence nearly all aspects of physiology and behavior, including sleep-wake cycles, cardiovascular activity, endocrinology, body temperature, renal activity, physiology of the gastro-intestinal tract, and hepatic metabolism. The master pacemaker is located in the suprachiasmatic nuclei, two small groups of neurons in the ventral part of the hypothalamus. However, most peripheral body cells contain self-sustained circadian oscillators with a molecular makeup similar to that of SCN (suprachiasmatic nucleus) neurons. This organization implies that the SCN must synchronize countless subsidiary oscillators in peripheral tissues, in order to coordinate cyclic physiology. In this review, we will discuss some recent studies on the structure and putative functions of the mammalian circadian timing system, but we will also point out some apparent inconsistencies in the currently publicized model for rhythm generation.
KeywordsCircadian Clock Clock Gene Period Length Circadian Oscillator Peripheral Clock
We would like to thank Nicolas Roggli for the artwork. Research from our own laboratory discussed in this review has been supported by Swiss National Science Foundation (grant to U.S.), the State of Geneva, the NCCR program “Frontiers in Genetics,” the Bonnizzi Theler Stiftung, and the Louis Jeantet Foundation of Medicine. F.G. received a postdoctoral fellowship from the Fondation pour la Recherche Médicale (France).
- Bondy SC, Naderi S (1994) Contribution of hepatic cytochrome P450 systems to the generation of reactive oxygen species. Biochem Pharmacol 48:155–159Google Scholar
- Gerkema MP, van der Leest F (1991) Ongoing ultradian activity rhythms in the common vole, Microtus arvalis, during deprivations of food, water and rest. J Comp Physiol [A] 168:591–597Google Scholar
- Lavery DJ, Lopez-Molina L, Margueron R, Fleury-Olela F, Conquet F, Schibler U, Bonfils C (1999) Circadian expression of the steroid 15 alpha-hydroxylase (Cyp2a4) and coumarin 7-hydroxylase (Cyp2a5) genes in mouse liver is regulated by the PAR leucine zipper transcription factor DBP. Mol Cell Biol 19:6488–6499PubMedGoogle Scholar
- Yoo SH, Yamazaki S, Lowrey PL, Shimomura K, Ko CH, Buhr ED, Siepka SM, Hong HK, Oh WJ, Yoo OJ, et al (2004) PERIOD2:LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci USA 101:5339–5346CrossRefPubMedGoogle Scholar