Orphan nuclear receptors, molecular clockwork, and the entrainment of peripheral oscillators.

Jan 10, 2004Novartis Foundation symposium

Orphan nuclear receptors and the body’s internal clock controlling timing in organs

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Circadian Biology on OpenScience ↗PubMed ↗

Abstract

REV-ERBalpha regulates the cyclic expression of Bmal1 and Clock in the molecular clockwork.

Orphan nuclear receptor REV-ERBalpha links the positive and negative components of the molecular oscillator.
The expression of REV-ERBalpha is controlled by the molecular oscillator, being activated by BMAL1 and CLOCK, and repressed by PERIOD1/2 and CRYPTOCHROME1/2.
Circadian oscillators exist in various peripheral tissues, which can dampen without a functional suprachiasmatic nucleus (SCN).
The SCN is thought to synchronize peripheral clocks primarily through feeding times.
Other factors such as body temperature rhythms and hormone secretion may also influence peripheral clock timing.

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Here we summarize our work on two aspects of circadian timing: the roles of orphan nuclear receptors in the molecular clockwork, and phase entrainment of peripheral oscillators. With reference to the former, studies on cis-acting regulatory elements within the Bmal1 promoter revealed that REV-ERBalpha, an orphan nuclear receptor provides a link between the positive and negative limbs of the molecular oscillator. Specifically, REV-ERBalpha controls the cyclic transcription of Bmal1 and Clock, the positive limb components. In turn, the circadian expression of Rev-Erbalpha itself is driven directly by the molecular oscillator: it is activated by BMAL1 and CLOCK, and repressed by PERIOD1/2 and CRYPTOCHROME1/2 proteins (the negative limb members). With regard to phase entrainment, it was initially believed that only the suprachiasmatic nucleus (SCN) was capable of generating circadian rhythms. However, circadian oscillators have recently been discovered in many peripheral tissues. In the absence of a functional SCN pacemaker, these peripheral clocks dampen after a few days. Hence, the SCN must periodically synchronize these subsidiary timekeepers. It may accomplish this task mostly through an indirect route: namely, by setting the time of feeding. In addition to feeding cycles, body temperature rhythms and cyclically secreted hormones might also serve as zeitgebers for peripheral clocks.

Orphan nuclear receptors, molecular clockwork, and the entrainment of peripheral oscillators.

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