Circadian Gene Expression in Individual Fibroblasts

Nagoshi, Emi; Saini, Camille; Bauer, Christoph; Laroche, Thierry; Naef, Félix; Schibler, Ueli

doi:10.1016/j.cell.2004.11.015

Cited by 876 publications

(415 citation statements)

References 36 publications

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“…This observation was reproducible when Rat-1 fibroblasts were used (unpublished data; Balsalobre et al, 1998). A very recent report demonstrated that in vitro cultured fibroblasts harbor self-sustained and cell-autonomous circadian clocks similar to those operative in SCN neurons (Nagoshi et al, 2004). Therefore, the high amplitude of Per1 mRNA oscillation in peripheral tissues largely depends on the extracellular environment such as blood-borne factors and body temperature, which changes cyclically around the clock, rather than on the cell autonomous core clock.…”

supporting

confidence: 54%

Molecular Mechanism of Cell-autonomous Circadian Gene Expression ofPeriod2, a Crucial Regulator of the Mammalian Circadian Clock

Akashi¹,

Ichise²,

Mamine

et al. 2006

MBoC

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Although circadian transcription of Period2 (Per2) is fundamental for the generation of circadian rhythm, the molecular mechanism remains unclear. Here we report that cell-autonomous circadian transcription of Per2 is driven by two transcriptional elements, one for rhythm generation and the other for phase control. The former contains the E-box-like sequence (CACGTT) that is sufficient and indispensable to drive oscillation, and indeed circadian transcription factors site-specifically bind to it. Furthermore, the nature of this atypical E-box is different from that of the classical circadian E-box. The current feedback loop model is based mainly on Period1. Our results provide not only compelling evidence in support of this model but also an explanation for a general basic mechanism to produce various patterns in the phase and amplitude of cell-autonomous circadian gene expression. INTRODUCTIONIn nearly all organisms, behavioral and physiological processes display ϳ24 h rhythms that are controlled by circadian pacemakers (Pittendrigh, 1993). The circadian organization of physiology and behavior in mammals is governed by the suprachiasmatic nuclei (SCN), a defined pair of cell clusters in the anteroventral hypothalamus (Ralph et al., 1990). Circadian clocks can count time only approximately and must be adjusted every day by the photoperiod in order to be in harmony with the outside world (Menaker, 2003). Circadian oscillators also exist in most peripheral cells and even in cultured cells (Balsalobre et al., 1998;Yamazaki et al., 2000). It is thought that the phase of these peripheral timekeepers is reset by signals regulated by the SCN pacemaker (Akashi and Nishida, 2000;Schibler and Sassone-Corsi, 2002).The molecular makeup of circadian clocks has been the subject of intense genetic and biochemical investigation in various organisms, including cyanobacteria, Neurospora, higher plants, Drosophila, and mammals (Dunlap, 1999;Kondo and Ishiura, 2000;Allada et al., 2001;Williams and Sehgal, 2001;Young and Kay, 2001;Reppert and Weaver, 2002). Over the last several years, orthologues of most Drosophila circadian clock genes have been cloned from mammals (Albrecht and Eichele, 2003;Lowrey and Takahashi, 2004). Although mPer2 was literally cloned as a secondary mammalian period gene (Albrecht et al., 1997;Takumi et al., 1998), gene-knockout analysis revealed that an mPer2 mutant displays a loss of circadian rhythmicity, revealing a prominent role for mPER2 in the mammalian clock (Zheng et al., 1999). Additionally familial advanced sleep phase syndrome has been attributed to a missense mutation in hPer2 (Toh et al., 2001). These studies demonstrate that a robust circadian fluctuation in Per2 transcription is an essential event for the generation of circadian rhythm.Circadian oscillators appear to have been highly conserved throughout evolution and to involve transcriptiontranslation negative feedback loops for the regulation of clock genes (Dunlap, 1999;Young and Kay, 2001). In mammals, in vitro studies have shown that th...

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supporting

confidence: 54%

Molecular Mechanism of Cell-autonomous Circadian Gene Expression ofPeriod2, a Crucial Regulator of the Mammalian Circadian Clock

Akashi¹,

Ichise²,

Mamine

et al. 2006

MBoC

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“…Based on the observation that all examined cellular circadian oscillators in vertebrates have been shown to act in a self-sustained and cell-autonomous manner (2-5, 21), we favor the desynchronization over the damping hypothesis. Obviously, the only definitive way to discriminate between damping and desynchronization of peripheral vole oscillators would be to monitor circadian gene expression in individual cells, as has been accomplished for mouse, rat, and zebrafish cells cultured in vitro (3,4,21). Unfortunately, the real-time recording technologies required for such experiments are not available for cells within intact animals.…”

Section: Discussionmentioning

confidence: 99%

“…Central and peripheral oscillators have a similar molecular makeup (see above) and, accordingly, share many properties. For example, both operate in a cell-autonomous and selfsustained fashion (2)(3)(4)(5), and clock-gene mutations affecting period length shorten or lengthen the period of both behavioral cycles (driven by SCN neurons) and circadian gene expression in cultured fibroblast (6,7). Perhaps the most obvious difference between central and peripheral circadian oscillators lies in the mechanisms by which they are synchronized.…”

mentioning

confidence: 99%

Impact of behavior on central and peripheral circadian clocks in the common vole Microtus arvalis , a mammal with ultradian rhythms

Veen

Minh

Gos

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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In most mammals, daily rhythms in physiology are driven by a circadian timing system composed of a master pacemaker in the suprachiasmatic nucleus (SCN) and peripheral oscillators in most body cells. The SCN clock, which is phase-entrained by light-dark cycles, is thought to synchronize subsidiary oscillators in peripheral tissues, mainly by driving cyclic feeding behavior. Here, we examined the expression of circadian clock genes in the SCN and the liver of the common vole Microtus arvalis, a rodent with ultradian activity and feeding rhythms. In these animals, clock-gene mRNAs accumulate with high circadian amplitudes in the SCN but are present at nearly constant levels in the liver. Interestingly, highamplitude circadian liver gene expression can be elicited by subjecting voles to a circadian feeding regimen. Moreover, voles with access to a running wheel display a composite pattern of circadian and ultradian behavior, which correlates with low-amplitude circadian gene expression in the liver. Our data indicate that, in M. arvalis, the amplitude of circadian liver gene expression depends on the contribution of circadian and ultradian components in activity and feeding rhythms.circadian gene expression ͉ circadian rhythm ͉ peripheral clocks ͉ suprachiasmatic nucleus ͉ feeding rhythms A ccording to current belief, molecular circadian rhythms in mammals are generated by two interconnected feedback loops of clock-gene expression (1). In this model, period 1 (PER1), period 2 (PER2), cryptochrome 1 (CRY1), and cryptochrome 2 (CRY2), the members of the negative limb, form heterotypic protein complexes that repress transcription of their own genes by interfering with the activity of the transcription factors CLOCK and BMAL1, the members of the positive limb. The antiphasic circadian transcription cycles of positive-and negative-limb members are interlocked by the orphan nuclear receptor REV-ERB␣, which periodically represses Bmal1 expression. It is not completely understood how the oscillations generated by this molecular clockwork circuitry are translated into overt rhythms in physiology and behavior, but mutations in circadian clock genes lead to behavioral arrhythmicity or periodlength changes (1).The mammalian circadian timing system has a hierarchical structure, in that a central pacemaker in the suprachiasmatic nucleus (SCN) coordinates peripheral clocks in most peripheral cells. Central and peripheral oscillators have a similar molecular makeup (see above) and, accordingly, share many properties. For example, both operate in a cell-autonomous and selfsustained fashion (2-5), and clock-gene mutations affecting period length shorten or lengthen the period of both behavioral cycles (driven by SCN neurons) and circadian gene expression in cultured fibroblast (6, 7). Perhaps the most obvious difference between central and peripheral circadian oscillators lies in the mechanisms by which they are synchronized. Whereas the phase of the SCN master pacemaker is entrained primarily by the photoperiod (8, 9), that of peri...

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“…This oscillator is self-sustained; it elicits circadian rhythm outputs with very little damping (5). Peripheral oscillators reside in almost every cell in the body (6); self-sustained independent circadian oscillators have been demonstrated in individual fibroblasts in cultures (7)(8)(9). When disconnected from the master oscillator, peripheral oscillators dampen quickly, probably as a result of desynchronization among individual cells (8).…”

mentioning

confidence: 99%

Circadian time-keeping during early stages of development

Ziv¹,

Gothilf

2006

Proc. Natl. Acad. Sci. U.S.A.

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The zebrafish pineal gland is a photoreceptive organ containing an intrinsic central circadian oscillator, which drives daily rhythms of gene expression and the melatonin hormonal signal. Here we investigated the effect of light, given at early developmental stages before pineal gland formation, on the pineal circadian oscillator. Embryos that were exposed to light at 0 -6, 10 -13, or 10 -16 h after fertilization exhibited clock-controlled rhythms of arylalkylamine-N-acetyltransferase (zfaanat2) mRNA in the pineal gland during the third and fourth day of development. This rhythm was absent in embryos that were placed in continuous dark within 2 h after fertilization (before blastula stage). Differences in the phases of these rhythms indicate that they are determined by the time of illumination. Light treatments at these stages also caused a transient increase in period2 mRNA levels, and the development of zfaanat2 mRNA rhythm was abolished by PERIOD2 knock-down. These results indicate that light exposure at early developmental stages, and light-induced expression of period2, are both required for setting the phase of the circadian clock. The 24-h rhythm is then maintained throughout rapid proliferation and, remarkably, differentiation.AANAT ͉ light ͉ period2 ͉ pineal ͉ zebrafish

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Circadian Gene Expression in Individual Fibroblasts

Cited by 876 publications

References 36 publications

Molecular Mechanism of Cell-autonomous Circadian Gene Expression ofPeriod2, a Crucial Regulator of the Mammalian Circadian Clock

Molecular Mechanism of Cell-autonomous Circadian Gene Expression ofPeriod2, a Crucial Regulator of the Mammalian Circadian Clock

Impact of behavior on central and peripheral circadian clocks in the common vole Microtus arvalis , a mammal with ultradian rhythms

Circadian time-keeping during early stages of development

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