Circadian rhythms from multiple oscillators: lessons from diverse organisms

Key Points

  • Daily rhythms in biochemical, cellular and behavioural activities are controlled by the biological clock, which consists of one or more endogenous oscillators.

  • The clock exerts its effects on a wide variety of processes, ranging from development in fungi, cell division in the marine protist Gonyaulax polyedra, photosynthesis in plants, sleep in animals, to cognitive functions in humans. Although circadian rhythms are present in different organisms, several aspects of the clock mechanism, and its complexity, are not conserved among these organisms.

  • In prokaryotic and eukaryotic microorganisms, the circadian clock system seems to consist of several oscillators. These oscillators might respond to different environmental signals and direct rhythms in specific genes and behaviours. The coupling of oscillators is thought to provide stability and precision to the timing mechanism.

  • In eukaryotes with differentiated tissues, a network of cell autonomous oscillators is found not within a single cell, but among cells in different tissue types. The clock system in eukaryotes also regulates rhythms in diverse biological processes, but these rhythms can be specific to different tissue types.

  • In mammals and birds, a circadian pacemaker in the brain responds to input from the environment and coordinates overt rhythmicity throughout the peripheral tissues.

  • In mammals, lesions and metabolic and electrophysiological studies have provided incontrovertible evidence that the SCN of the hypothalamus serves as the master circadian pacemaker. This pacemaker can coordinate rhythmicity in downstream cells and tissues.

  • In non-mammalian vertebrates, the circadian clock system seems to be more complex. In birds, the circadian system consists of at least three anatomically distinct circadian pacemakers; the retina, the pineal gland and an avian homologue of the mammalian SCN.

  • In Drosophila melanogaster, the hierarchal model of a central pacemaker setting the time of peripheral oscillators does not hold; virtually all tissues harbour circadian oscillators that can be entrained directly by light.

  • So, the need for a centralized pacemaker to entrain peripheral oscillators in organisms seems to be dependent on the ability of peripheral tissues to be directly entrained.


The organization of biological activities into daily cycles is universal in organisms as diverse as cyanobacteria, fungi, algae, plants, flies, birds and man. Comparisons of circadian clocks in unicellular and multicellular organisms using molecular genetics and genomics have provided new insights into the mechanisms and complexity of clock systems. Whereas unicellular organisms require stand-alone clocks that can generate 24-hour rhythms for diverse processes, organisms with differentiated tissues can partition clock function to generate and coordinate different rhythms. In both cases, the temporal coordination of a multi-oscillator system is essential for producing robust circadian rhythms of gene expression and biological activity.

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Figure 1: Circadian oscillators are controlled through a common mechanism.
Figure 2: The cyanobacterial periodosome model.
Figure 3: Multiple oscillators in the Neurospora crassa cell.
Figure 4: Molecular interactions in mammalian circadian-feedback loops.
Figure 5: A comparison of avian and mammalian pacemaker organization.
Figure 6: The Drosophila melanogaster circadian system.


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The authors are members of the Center for Research on Biological Clocks at Texas A&M University, Houston, USA. The work described in this review from the authors' laboratories was funded by the US National Institutes of Health, including an NINDS Program Project Grant and an NIEHS Center Grant.

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Correspondence to Deborah Bell-Pedersen.

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A circadian clock is a 24-hour timing mechanism that is composed of molecular oscillators.


A biological rhythm with a 24-hour period that persists in constant conditions.


A system of components that interact to produce a rhythm with a definable period length. A circadian oscillator can drive a rhythmic output, but requires other oscillators (pacemakers) for its entrainment and/or function. A circadian oscillator can therefore be self-sustained, but cannot operate properly independently of other oscillators.


The process by which an environmental rhythm, such as the light–dark cycle, regulates the period and phase relationship of a self-sustained oscillator.


An oscillator that drives an output and/or entrains another oscillator. A circadian pacemaker is a specialized oscillator that operates independently of other oscillators to drive rhythmic outputs, either directly or through other oscillators, and is entrained by environmental cues.


A small region of the brain that sits on top of the optic chiasm in the anteroventral region of the hypothalamus. Each of the bilaterally paired nuclei that comprise the SCN contains 8,000–10,000 cells packed together.


The time after which a defined phase of an oscillation (such as a peak or trough) recurs.


A structure in a prokaryotic cell that is composed of chromosomal DNA and its associated chromatin-like scaffolding proteins.


The instantaneous state of an oscillation relative to a reference point.


The portion of a circadian day that is spent in constant darkness, which corresponds to the midday phase of a light–dark cycle.


Members of a family of sigma factor proteins that are responsible for conferring promoter-specific contacts on the RNA polymerase enzyme of eubacteria, thereby allowing specific genes to be transcribed.


Asexually produced haploid fungal spores that are formed on a specialized aerial hypha — the conidiophore — that rises above the substratum.


Pertaining to elements that are dissolved in the blood or body fluid, typically serum.


The part of the brain that lies below the thalamus, forming the main portion of the ventral region of the diencephalon and functioning to regulate bodily temperature, certain metabolic processes and other autonomic activities.


Refers to a part of the autonomic nervous system that generally has excitatory function and regulates heart rate and blood pressure.


A family of visual pigments.


The part of an insect's gastrointestinal tract that excretes nitrogenous waste and maintains ionic balance.

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Bell-Pedersen, D., Cassone, V., Earnest, D. et al. Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nat Rev Genet 6, 544–556 (2005).

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