Biomedical subjects
Publications and source records attributed to Ueli Schibler.
In some simple protozoans and unicellular algae, the cell cycle clock is strongly influenced by the circadian clock, such that mitotic cell division takes place only at certain times of the day. Now, as Schibler reports in his Perspective, new work on regenerating liver cells in mice (Matsuo et al.) reveals that the cell cycle clock of mammalian cells is also under the yoke of the master circadian oscillator.
Peripheral cells from mammalian tissues, while perfectly capable of circadian rhythm generation, are not light sensitive and thus have to be entrained by nonphotic cues. Feeding time is the dominant zeitgeber for peripheral mammalian clocks: Daytime feeding of nocturnal laboratory rodents completely inverts the phase of circadian gene expression in many tissues, including liver, heart, kidney, and pancreas, but it has no effect on the SCN pacemaker. It is thus plausible that in intact animals, the SCN synchronizes peripheral docks primarily through temporal feeding patterns that are imposed through behavioral rest-activity cycles. In addition, body temperature rhythms, which are themselves dependent on both feeding patterns and rest-activity cycles, can sustain circadian, clock gene activity in vivo and in vitro. The SCN may also influence the phase of rhythmic gene expression in peripheral tissues through direct chemical pathways. In fact, many chemical signals induce circadian gene expression in tissue culture cells. Some of these have been shown to elicit phase shifts when injected into intact animals and are thus candidates for physiologically relevant timing cues. While the response of the SCN to light is strictly gated to respond only during the night, peripheral oscillators can be chemically phase shifted throughout the day. For example, injection of dexamethasone, a glucocorticoid receptor agonist, resets the phase of circadian liver gene expression during the entire 24-h day. Given the bewildering array of agents capable of influencing peripheral clocks, the identification of physiologically relevant agents used by the SCN to synchronize peripheral clocks will clearly be an arduous undertaking. Nevertheless, we feel that experimental systems by which this enticing problem can be tackled are now at hand.
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.
The mammalian circadian timing system is composed of almost as many individual clocks as there are cells. These countless oscillators have to be synchronized by a central pacemaker to coordinate temporal physiology and behavior. Recently, there has been some progress in understanding the relationship and communication mechanisms between central and peripheral clocks.
BACKGROUND: Low-amplitude temperature oscillations can entrain the phase of circadian rhythms in several unicellular and multicellular organisms, including Neurospora and Drosophila. Because mammalian body temperature is subject to circadian variations of 1 degrees C-4 degrees C, we wished to determine whether these temperature cycles could serve as a Zeitgeber for circadian gene expression in peripheral cell types. RESULTS: In RAT1 fibroblasts cultured in vitro, circadian gene expression could be established by a square wave temperature rhythm with a (Delta)T of 4 degrees C (12 hr 37 degrees C/12 hr 33 degrees C). To examine whether natural body temperature rhythms can also affect circadian gene expression, we first measured core body temperature cycles in the peritoneal cavities of mice by radiotelemetry. We then reproduced these rhythms with high precision in the liquid medium of cultured fibroblasts for several days by means of a homemade computer-driven incubator. While these "in vivo" temperature rhythms were incapable of establishing circadian gene expression de novo, they could maintain previously induced rhythms for multiple days; by contrast, the rhythms of control cells kept at constant temperature rapidly dampened. Moreover, circadian oscillations of environmental temperature could reentrain circadian clocks in the livers of mice, probably via the changes they imposed upon both body temperature and feeding behavior. Interestingly, these changes in ambient temperature did not affect the phase of the central circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. CONCLUSIONS: We postulate that both endogenous and environmental temperature cycles can participate in the synchronization of peripheral clocks in mammals.
Mammalian circadian rhythms are generated by a feedback loop in which BMAL1 and CLOCK, players of the positive limb, activate transcription of the cryptochrome and period genes, components of the negative limb. Bmal1 and Per transcription cycles display nearly opposite phases and are thus governed by different mechanisms. Here, we identify the orphan nuclear receptor REV-ERBalpha as the major regulator of cyclic Bmal1 transcription. Circadian Rev-erbalpha expression is controlled by components of the general feedback loop. Thus, REV-ERBalpha constitutes a molecular link through which components of the negative limb drive antiphasic expression of components of the positive limb. While REV-ERBalpha influences the period length and affects the phase-shifting properties of the clock, it is not required for circadian rhythm generation.
Biological rhythms are driven in mammals by a central circadian clock located in the suprachiasmatic nucleus (SCN). Light-induced phase shifting of this clock is correlated with phosphorylation of CREB at Ser133 in the SCN. Here, we characterize phosphorylation of CREB at Ser142 and describe its contribution to the entrainment of the clock. In the SCN, light and glutamate strongly induce CREB Ser142 phosphorylation. To determine the physiological relevance of phosphorylation at Ser142, we generated a mouse mutant, CREB(S142A), lacking this phosphorylation site. Light-induced phase shifts of locomotion and expression of c-Fos and mPer1 in the SCN are significantly attenuated in CREB(S142A) mutants. Our findings provide genetic evidence that CREB Ser142 phosphorylation is involved in the entrainment of the mammalian clock and reveal a novel phosphorylation-dependent regulation of CREB activity.
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