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Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001.

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Neuroscience. 2nd edition.

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Box BMolecular Mechanisms of Biological Clocks

Virtually all plants and animals adjust their physiology and behavior to the 24-hour day-night cycle under the governance of circadian clocks. Molecular biological studies have now indicated much about the genes and proteins that make up the machinery of these clocks, a story that began nearly 30 years ago.

In the early 1970s, Ron Konopka and Seymour Benzer, working at the California Institute of Technology, discovered three mutant strains of fruit flies whose circadian rhythms were abnormal. Further analysis showed the mutants to be alleles of a single locus, which Konopka and Benzer called the period or per gene. In the absence of normal environmental cues (that is, in constant light or dark), wild-type flies have periods of activity geared to a 24-hour cycle; pers mutants have 19 hour rhythms, per1 mutants have 29-hour rhythms, and per0 mutants have no apparent rhythm. About 10 years later, Michael Young at Rockefeller University and Jeffrey Hall and Michael Rosbash at Brandeis University independently cloned the first of the three per genes. Cloning a gene does not necessarily reveal its function, however, and so it was in this case. Nonetheless, the gene product PER, a nuclear protein, is found in many Drosophila cells pertinent to the production of the fly's circadian rhythms. Moreover, normal flies show a circadian variation in the amount of per mRNA and PER protein, whereas per0 flies, which lack a circadian rhythm, do not show this circadian rhythmicity of gene expression.

Many of the genes and proteins responsible for circadian rhythms in fruit flies have now been discovered in mammals. In mice, the circadian clock arises from the temporally regulated activity of proteins (in capital letters) and genes (in italics), including CRY (cryptochrome), CLOCK (C) (Circadian locomotor output cycles kaput), BMAL1 (B) (brain and muscle, ARNT-like), PER1 (Period1), PER2 (Period2), PER3 (Period3), and vasopressin prepropressophysin (VP) (clock controlled genes; ccg). These genes and their proteins give rise to transcription/translation autoregulatory feedback loops with both excitatory and inhibitory components (see figure). The key points to understanding this system are: (1) that the concentrations of BMAL1 (B) and the three PER proteins cycle in counterpoint; (2) that PER2 is a positive regulator of the Bmal1 loop; and (3) that CRY is a negative regulator of the period and cryptochrome loops. The two positive components of this loop are influenced, albeit indirectly, by light or temperature.

At the start of the day, the transcription of Clk and Bmal1 commencences, and the proteins CLOCK (C) and BMAL1 (B) are synthesized in tandem. When the concentrations of C and B increase sufficiently, they associate as dimers and bind to regulatory DNA sequences (E-boxes) that act as a circadian transcriptional enhancers of the genes Cry, Per 1, 2, and 3 and CCG. As a result, the proteins PER1, 2, and 3, CRY, and proteins such as VP are produced. These proteins then diffuse from the nucleus into the cytoplasm, where they are modified.

Although the functions of PER1 and PER3 remain to be elucidated, when the cytoplasmic concentrations of PER2 and CRY increase, they associate as CRY- PER2, and diffuse back into the nucleus. Here, PER2 stimulates the synthesis of C, and B, and CRY binds to C-B dimers, inhibiting their ability to stimulate the synthesis of the other genes. The complete time course of these feedback loops is 24 hours.

Image ch28fbb1.jpg

Diagram illustrating molecular feedback loop that governs circadian clocks. (After Okamura et al., 1999.)


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From: The Circadian Cycle of Sleep and Wakefulness

Copyright © 2001, Sinauer Associates, Inc.


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