The ins and outs of circadian timekeeping

doi:10.1016/S0959-437X(99)00009-X

Current Opinion in Genetics & Development

Volume 9, Issue 5, 1 October 1999, Pages 588-594

https://doi.org/10.1016/S0959-437X(99)00009-X Get rights and content

Abstract

Recent research in Drosophila and in mammals has generated fascinating new models for how circadian clocks in these organisms are reset by light and how these clocks, in turn, direct circadian outputs. Though light perception by the central clock is ocular in mammals, it probably proceeds via a mechanism separate from traditional visual transduction. In Drosophila, one mechanism is non-ocular and is in fact present in many different tissues. In both organisms, the cryptochrome family of photoreceptor-like molecules plays a role in the circadian clock, though their function is incompletely understood. Moreover, although a master clock resides in the brain, a functional clock appears to reside in most cells of the body. In these tissues, at least some output genes are controlled at the transcriptional level directly by clock proteins; others appear to be regulated by cascades of circadian transcription factors. Taken together, these observations are reshaping thinking about inputs and outputs of metazoan circadian clocks.

Introduction

Circadian clocks have been conserved in many instances throughout the evolution of living organisms, allowing bacteria, animals, and plants to adapt their physiological needs to the time of day in an anticipatory fashion. These pacemakers regulate a plethora of processes. In cyanobacteria, for example, the majority of promoters of metabolic genes appear to exhibit cyclical expression [1]. In mammals, physiological processes like sleep–wake cycles, body temperature, heartbeat, and many aspects of liver, kidney, and digestive tract physiology are all under circadian control [2]. The fashion in which clocks control such diverse functions in metazoan organisms remains a largely unexplored question in the field of chronobiology, and will be one focus of our review.

Circadian clocks continue to ‘tell time’ in the absence of environmental time cues such as changes in light intensity. The period length (‘Tau’ or ‘τ’ in clock parlance) of each cycle is approximately, 24 hours under constant conditions (e.g. constant darkness). Hence, in order for the circadian clock to tell time accurately, it must be readjusted (or phase shifted) every day by the light regimen (or photoperiod). The mechanism by which light signals entrain the clock is another topic of intense interest, and will be our other focus.

Section snippets

Central clock mechanisms: a brief summary

In all cases examined to date, circadian clocks have been cell-autonomous: a single cell can generate and maintain self-sustained circadian oscillations. The molecular basis for these rhythms may rely on a negative feedback loop in which clock proteins negatively regulate their own abundance or activity. This regulation may occur both at the transcriptional and at the post-transcriptional level. For example, in the bread mold Neurospora crassa, the Frequency protein negatively regulates its own

Communication between the central pacemaker and peripheral clocks

Complex multicellular organisms appear to have central clocks that reside in discrete ‘pacemaker tissues’ in the central nervous system. In these tissues, individual independent clocks in each cell cooperate to generate an as-yet-unknown timing signal used by the body as a whole. In Drosophila, these are composed of eight lateral neurons in the brain [12]. In lower vertebrates, the pineal gland can play a similar role, and in mammals the suprachiasmatic nucleus (SCN) of the hypothalamus is the

Regulation of circadian clock outputs

Recent studies have also shed light on the molecular mechanisms by which the central clock may control circadian output genes. Some of these downstream genes appear to be regulated by the same cis-acting DNA elements and transcription factors that govern the expression of the central clock genes themselves. The arginine vasopressin gene, expressed in SCN neurons, provides an excellent example of such a strategy. The product of this gene is responsible for the circadian regulation of salt and

Light as an input to the circadian clock

How light changes the phase of the circadian clock — or ‘entrains the clock’, in chronobiological terms — is another subject of intense recent investigation. In Drosophila, not only do autonomous clocks exist in many peripheral tissues, but they are also light-entrainable in isolated body parts [17]. Moreover, ablation of the eyes has only a minor effect on photo-entrainment in this organism [32]. Taken together, these observations strongly suggest that Drosophila clocks are reset by light via

Conclusions and perspectives

This review has attempted to simplify the discussion of circadian timing systems by dividing it into three parts: an input pathway leading to the clock, a pacemaker, and an output pathway emanating from it. Research performed during the last few years, however, has shown that these components are not completely distinct. For example, cryptochrome genes, thought to be photoreceptors, were found to be vital to clock function in mammals; and the DBP output gene was found to change the period of

Acknowledgements

Special thanks to M Rosbash and J Ripperger for critical reading of this manuscript, and to M Menaker, H Okamura, K Honma, J Dunlap, and I Edery for access to manuscripts in press.

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

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View full text

ReviewThe ins and outs of circadian timekeeping

Abstract

Introduction

Section snippets

Central clock mechanisms: a brief summary

Communication between the central pacemaker and peripheral clocks

Regulation of circadian clock outputs

Light as an input to the circadian clock

Conclusions and perspectives

Acknowledgements

References and recommended reading

Cell

Curr Opin Genet Dev

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Cell

Neuron

Cell

Neurosci Lett

Cell

Neuron

Brain Res

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Cell

Cell

Cell

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Cyanobacterial circadian rhythms

Annu Rev Plant Physiol Plant Mol Biol

Chronobiology in endocrinology

Ann 1st Super Sanita

Expression of a gene cluster kaiABC as a circadian feedback process in cyanobacteria

Science

PER and TIM inhibit the DNA binding activity of a dCLOCK-CYC/dBMAL1 heterodimer without disrupting formation of the heterodimer: a basis for circadian transcription

Mol Cell Biol

Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim

Science

Expression of the period clock gene within different cell types in the brain of Drosophila adults and mosaic analysis of these cells’ influence on circadian behavioral rhythms

J Neurosci

Molecular neurobiology and genetics of circadian rhythms in mammals

Annu Rev Neurosci

Rhythmic regulation of retinal melatonin: metabolic pathways, neurochemical mechanisms, and the ocular circadian clock

Cell Mol Neurobiol

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Science

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Proc Natl Acad Sci USA

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Zebrafish Clock rhythmic expression reveals independent peripheral circadian oscillators

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Review
The ins and outs of circadian timekeeping