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  • Review Article
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Molecular mechanisms and physiological importance of circadian rhythms

Nature Reviews Molecular Cell Biology volume 21, pages 67–84 (2020)Cite this article

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Abstract

To accommodate daily recurring environmental changes, animals show cyclic variations in behaviour and physiology, which include prominent behavioural states such as sleep–wake cycles but also a host of less conspicuous oscillations in neurological, metabolic, endocrine, cardiovascular and immune functions. Circadian rhythmicity is created endogenously by genetically encoded molecular clocks, whose components cooperate to generate cyclic changes in their own abundance and activity, with a periodicity of about a day. Throughout the body, such molecular clocks convey temporal control to the function of organs and tissues by regulating pertinent downstream programmes. Synchrony between the different circadian oscillators and resonance with the solar day is largely enabled by a neural pacemaker, which is directly responsive to certain environmental cues and able to transmit internal time-of-day representations to the entire body. In this Review, we discuss aspects of the circadian clock in Drosophila melanogaster and mammals, including the components of these molecular oscillators, the function and mechanisms of action of central and peripheral clocks, their synchronization and their relevance to human health.

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Fig. 1: The Drosophila melanogaster molecular clock.
Fig. 2: The expression of several circadian clock genes oscillates over the day–night cycle.
Fig. 3: The molecular circadian clock in mammals is formed by interlocking transcription–translation feedback loops.
Fig. 4: Peripheral clocks in Drosophila melanogaster.
Fig. 5: The central clock and selected peripheral clocks in humans.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (GM054339 and NS053087) and Calico Lifesciences LLC to M.W.Y.

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  1. Laboratory of Genetics, The Rockefeller University, New York, NY, USA

    Alina Patke, Michael W. Young & Sofia Axelrod

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Contributions

M.W.Y. established the scope of the review. A.P. and S.A. researched data and wrote the subsections on mammals and flies, respectively, and jointly contributed to the remaining subsections. All authors made substantial contributions to the discussion and revision of the manuscript prior to submission.

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Correspondence to Michael W. Young.

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Research in the laboratory of M.W.Y is partly funded by Calico Lifesciences LLC.

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Supplementary information

Glossary

Circadian rhythmicity

A physiological or behavioural oscillation with a period of ~24 h, which is sustained in constant conditions and entrainable by external cues such as light.

Eclosion

The emergence of an insect from the pupal case.

E/E′-box

The DNA element CACGT(T/G), which is bound by the basic helix–loop–helix transcription factors CLOCK–BMAL1.

D-box

(DBP response element). A DNA element (TTATG(C/T)AA) bound by transcription regulators of the proline and acidic amino acid-rich–basic leucine zipper family (DBP, TEF, HLF) and E4BP4 (also known as NFIL3).

Basic leucine zipper

(bZip). A protein domain common in many DNA-binding proteins.

Topologically associating domains

Genomic regions with extensive internal chromatin interactions (such as between promoters and distal enhancers) and fewer contacts with neighbouring regions.

Delayed sleep phase disorder

A circadian rhythm sleep disorder characterized by a delay in the major sleep episode relative to the desired sleep time.

Efferent projections

Axons exiting from a particular region such as the suprachiasmatic nuclei.

Prothoracic gland

An endocrine gland in certain insects regulating moulting by secretion of steroid hormones such as ecdysone.

Oenocytes

Pheromone-producing secretory cells found in most insects.

Malpighian tubules

An excretory and osmoregulatory system used by some invertebrates; Malpighian tubules are functionally similar to the mammalian kidney.

Proboscis

A flexible and tubular mouth part used by many insect species for feeding.

Short neuropeptide F

A signalling molecule released by subpopulations of neurons including some clock neurons; orthologue to mammalian neuropeptide Y.

Cistrome

The genome-wide set of cis-acting targets of a trans-acting factor, for example, the in vivo genome-wide binding locations of a transcription factor.

Ionotropic receptors

Ligand-gated ion channels, which form pores for specific ions in the plasma membrane upon binding of a specific extracellular ligand.

Chordotonal organ

A sensory organ found along the body wall of insects and crustaceans, which operates as an auditory organ, a position and movement sensor or a sensor of wind, gravity or temperature.

Parabiosis

The surgical joining of two organisms to form one shared physiological system.

Chronotype

The intrinsic preference of an individual with regards to the timing of rest and activity during a 24-h period, including early (also referred to as morningness), intermediate or late (also referred to as eveningness).

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Patke, A., Young, M.W. & Axelrod, S. Molecular mechanisms and physiological importance of circadian rhythms. Nat Rev Mol Cell Biol 21, 67–84 (2020). https://doi.org/10.1038/s41580-019-0179-2

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  • DOI: https://doi.org/10.1038/s41580-019-0179-2

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