The mammalian circadian clock

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Abstract

Organisms populating the earth are under the steady influence of daily and seasonal changes resulting from the planet’s rotation and orbit around the sun. This periodic pattern most prominently manifested by the light–dark cycle has led to the establishment of endogenous circadian timing systems that synchronize biological functions to the environment. The mammalian circadian system is composed of many individual, tissue-specific clocks. To generate coherent physiological and behavioral responses, the phases of this multitude of clocks are orchestrated by the master circadian pacemaker residing in the suprachiasmatic nuclei of the brain. Genetic, biochemical and genomic approaches have led to major advances in understanding the molecular and cellular basis of mammalian circadian clock components and mechanisms.

Introduction

Persistent exposure to jetlag, shift work and short winter days in northern latitudes can cause disruption of the circadian clock 1.•, 2.. What is the circadian clock and what is its purpose? The circadian clock prepares the body for tasks that typically occur in the course of a day. For predator animals to successfully chase after prey requires that energy-generating organs and muscles are primed for peak performance at the time of the hunt. It thus makes sense that a broad spectrum of physiological parameters including the sleep–wake cycle, hormone secretion (e.g. adrenocorticotrophic hormone and cortisol), heart beat, renal blood flow and body temperature fluctuate with a period of ∼24 hours. To stalk prey, the hunter’s alertness (via its sense organs and brain) and agility (via its muscles and skeleton) need to be simultaneously optimized. This coordination of preparedness for function is immensely aided by the remarkable finding that there are circadian clocks in many organs [3] and cells that are ultimately coordinated by the clockwork of the suprachiasmatic nucleus (SCN) that is located in the ventral hypothalamus (Figure 1c) [4]. The SCN integrates signals from the visual system (e.g. the light–dark cycle) and from the periphery. Although most humans in our industrialized society have been affected by the side effects of circadian clock disruption, our understanding of circadian clock mechanisms is chiefly based on animal studies; hence this brief review of recent advances in this fascinating and very active field concentrates on work with animals, mostly mice. We do, however, comment on a small number of studies in humans that have reached the level of a ‘molecular explanation’. The commonly used experimental strategies for studying circadian clocks in mammals are explained in Figure 1.

Section snippets

Components of the clockwork

Over the past few years, the molecular models of the circadian clock have evolved as additional clock genes have been identified (for recent reviews, see 5., 6., 7., 8., 9., 10.). The central circadian clockwork consists of interwoven positive and negative feedback loops, or ‘limbs’ (Figure 2). The positive limb involves CLOCK/BMAL1 heterodimers, two basic helix–loop–helix transcriptional activators that bind to E-boxes located in the regulatory region of the period (per) and cryptochrome (cry)

Clock input and output

The elaborate design of the circadian clockwork residing in the SCN permits acceptance of input from the environment and production of output signals to peripheral clocks. The mechanism of light input is the subject of intense research but obviously involves the retina because eye loss in both humans and mice abolishes light entrainment. It had been shown that mice lacking cones or both rods and cones can still be entrained [16], suggesting that there are additional photoreceptors that mediate

Circadian clocks are found in many places

When the expression pattern of Per1 was first described, it was found that its transcript levels were oscillating not only in the SCN but also in the pars tuberalis and the retina [29]. Balsalobre et al. [30] made the striking observation that serum shock induced circadian gene expression in cultured mammalian cells. The initial observation of the existence of clocks in many cell types and organs has now rapidly expanded and led to the view that mammals have numerous peripheral clocks. A useful

The circadian transcriptome

As in many other areas of biomedical research, global gene expression profiling (e.g. using microarrays) has been applied to the circadian system. Such analyses included the SCN [38••], liver 38.••, 39.••, 40., 41., 42., heart [39••] as well as synchronized tissue culture cells onto which a circadian rhythm was imposed 43., 44.. These studies are a rich source of genes that play a role in all aspects of circadian physiology in the SCN and in peripheral clocks. Several general points have

Conclusions

In the course of the past few years, many substantial advances have been made in understanding the biology of the circadian clock. We have now a reasonably comprehensive model of the clock core mechanism but still lack a clear picture of the signaling pathways that transmit environmental cues to the core clock. Light input is at least in part mediated by a photopigment (melanopsin) located in retinal ganglion cells. Non-photic inputs may be hormonal and also may stem from the redox state of

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

We thank Henrik Oster for critical reading of the manuscript. U Albrecht is supported by the Swiss National Science Foundation, AETAS Foundation, the State of Fribourg and BrainTime (European Commission and the Swiss Office for Education and Science, QLG3-CT2002-01829). G Eichele is supported by the Max Planck Society and by BrainTime.

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