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At least 613 records · Page 34Linked to original sources
PubMed1999

The Goodwin oscillator: on the importance of degradation reactions in the circadian clock.

This article focuses on the Goodwin oscillator and related minimal models, which describe negative feedback schemes that are of relevance for the circadian rhythms in Neurospora, Drosophila, and probably also in mammals. The temperature behavior of clock mutants in Neurospora crassa and Drosophila melanogaster are well described by the Goodwin model, at least on a semi-quantitative level. A similar semi-quantitative description has been found for Neurospora crassa phase response curves with respect to moderate temperature pulses, heat shock pulses, and pulses of cycloheximide. A characteristic feature in the Goodwin and related models is that degradation of clock-mRNA and clock protein species plays an important role in the control of the oscillator's period. As predicted by this feature, recent experimental results from Neurospora crassa indicate that the clock (FRQ) protein of the long period mutant frq7 is degraded approximately twice as slow as the corresponding wild-type protein. Quantitative RT-PCR indicates that experimental frq7-mRNA concentrations are significantly higher than wild-type levels. The latter findings cannot be modeled by the Goodwin oscillator. Therefore, a threshold inhibition mechanism of transcription is proposed.

Algorithms↗
PubMed2006

FLOWERING LOCUS C-dependent and -independent regulation of the circadian clock by the autonomous and vernalization pathways.

BACKGROUND: The circadian system drives pervasive biological rhythms in plants. Circadian clocks integrate endogenous timing information with environmental signals, in order to match rhythmic outputs to the local day/night cycle. Multiple signaling pathways affect the circadian system, in ways that are likely to be adaptively significant. Our previous studies of natural genetic variation in Arabidopsis thaliana accessions implicated FLOWERING LOCUS C (FLC) as a circadian-clock regulator. The MADS-box transcription factor FLC is best known as a regulator of flowering time. Its activity is regulated by many regulatory genes in the "autonomous" and vernalization-dependent flowering pathways. We tested whether these same pathways affect the circadian system. RESULTS: Genes in the autonomous flowering pathway, including FLC, were found to regulate circadian period in Arabidopsis. The mechanisms involved are similar, but not identical, to the control of flowering time. By mutant analyses, we demonstrate a graded effect of FLC expression upon circadian period. Related MADS-box genes had less effect on clock function. We also reveal an unexpected vernalization-dependent alteration of periodicity. CONCLUSION: This study has aided in the understanding of FLC's role in the clock, as it reveals that the network affecting circadian timing is partially overlapping with the floral-regulatory network. We also show a link between vernalization and circadian period. This finding may be of ecological relevance for developmental programming in other plant species.

Arabidopsis↗
PubMed2005

Pulses of prolactin promoter activity depend on a noncanonical E-box that can bind the circadian proteins CLOCK and BMAL1.

Recent findings from our laboratory and those of others demonstrated that prolactin gene expression (PRL-GE) oscillates in single living mammotropes, but little information is available on the molecular processes that contribute to this phenomenon. To elucidate the source of this activity, we generated a series of constructs containing decreasing lengths of the PRL promoter fused to a luciferase reporter gene. These constructs were injected into single cells and assayed for photonic activity. We found pulse activity with all plasmids tested, even with the smallest promoter fragment of 331 bp. Sequence analysis of this fragment identified two potential E-boxes (elements known to bind CLOCK and BMAL1 circadian proteins). Furthermore, RT-PCR of PRL cells (pituitary, MMQ, and GH(3)) revealed expression of clock and bmal1 as well as five other clock genes (per1, per2, cry1, cry2, and tim), suggesting that the circadian system may function in PRL cells. Next, we mutated the core sequences of both E-boxes within the 2.5-kb PRL promoter and found that only mutation of the E-box133 completely abolished PRL-GE pulses. EMSAs revealed that CLOCK and BMAL1 were able to bind to the E-box133 site in vitro. Our results demonstrate that PRL-GE pulses are dependent on a specific E-box binding site in the PRL promoter. Moreover, the indication that CLOCK/BMAL1 can bind to this site suggests that these circadian proteins, either alone or in conjunction with other factors, may regulate intermittent PRL promoter activity in mammotropes, perhaps by acting as a temporal switch for the on/off expression of PRL.

ARNTL Transcription Factors↗
PubMed2006

Reciprocal regulation of brain and muscle Arnt-like protein 1 and peroxisome proliferator-activated receptor alpha defines a novel positive feedback loop in the rodent liver circadian clock.

Recent evidence has emerged that peroxisome proliferator-activated receptor alpha (PPARalpha), which is largely involved in lipid metabolism, can play an important role in connecting circadian biology and metabolism. In the present study, we investigated the mechanisms by which PPARalpha influences the pacemakers acting in the central clock located in the suprachiasmatic nucleus and in the peripheral oscillator of the liver. We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. We further demonstrate that fenofibrate induces circadian rhythm of clock gene expression in cell culture and up-regulates hepatic bmal1 in vivo. Together, these results provide evidence for an additional regulatory feedback loop involving BMAL1 and PPARalpha in peripheral clocks.

ARNTL Transcription Factors↗
PubMed2000

Tracking clock-shifted homing pigeons from familiar release sites.

Clock-shifted homing pigeons were tracked from familiar sites 17.1 km and 23.5 km from the home loft in Pisa, Italy, using an on-board route recorder. At the first release site, north of home, the majority of clock-shifted birds had relatively straight tracks comparable with those of control birds. At the second release site, south of home, the clock-shifted birds deflected in the direction predicted for the degree of clock shift, with many birds travelling some distance in the wrong direction before correcting their course. The possible role of large-scale terrain features in homing pigeon navigation is discussed.

Animals↗
PubMedDate not supplied

Downloading central clock information in Drosophila.

Pigment-dispersing factor (PDF) neuropeptide is an important neurochemical that carries circadian timing information originating from the central oscillator in Drosophila. Several core-clock factors function as upstream pdf regulators; the dClock and cycle genes control pdf transcription, whereas the period and timeless genes regulate post-translational processes of PDF via unknown mechanisms. For a downstream neural path, PDF most likely acts as a local modulator, which binds to its receptors that are possibly linked to Ras/MAPK signaling pathways. PDF receptor-containing cells seem to localize in the vicinity of nerve terminals from pace-making neurons. Although PDF is likely to be a principal clock-output factor, our recent evidence predicts the presence of other neuropeptides with rhythm-relevant functions. Furthermore, recent microarray screens have identified numerous potential clock-controlled genes, suggesting that diverse physiological processes might be affected by the biological clock system.

Animals↗
PubMed2004

Gating of the cAMP signaling cascade and melatonin synthesis by the circadian clock in mammalian retina.

Melatonin is synthesized in retinal photoreceptor cells and acts as a neuromodulator imparting photoperiodic information to the retina. The synthesis of melatonin is controlled by an ocular circadian clock and by light in a finely tuned mechanism that ensures that melatonin is synthesized and acts only at night in darkness. Here we report that the circadian clock gates melatonin synthesis in part by regulating the expression of the type 1 adenylyl cyclase (AC1) and the synthesis of cAMP in photoreceptor cells. This gating is effected through E-box-mediated transcriptional activation of the AC1 gene, which undergoes robust daily fluctuations that persist in constant illumination. The circadian control of the cAMP signaling cascade indicates that the clock has a more general and profound impact on retinal functions than previously thought. In addition, rhythmic control of AC1 expression was observed in other parts of the central circadian axis, the suprachiasmatic nucleus and pineal gland, but not in other brain areas examined. Thus, clock control of the cAMP signaling cascade may play a central role in the integration of circadian signals that control physiology and behavior.

ARNTL Transcription Factors↗
PubMed2006

Zebrafish arylalkylamine-N-acetyltransferase genes - targets for regulation of the circadian clock.

Daily rhythms of melatonin production are controlled by changes in the activity of arylalkylamine-N-acetyltransferase (AANAT). Zebrafish possess two aanats, aanat1 and aanat2; the former is expressed only in the retina and the latter is expressed in both the retina and the pineal gland. Here, their differential expression and regulation were studied using transcript quantification and transient and stable in vivo and in vitro transfection assays. In the pineal gland, the aanat2 promoter exhibited circadian clock-controlled activity, as indicated by circadian rhythms of Enhanced green fluorescent protein (EGFP) mRNA in AANAT2:EGFP transgenic fish. In vivo transient expression analyses of the aanat2 promoter indicated that E-box and photoreceptor conserved elements (PCE) are required for expression in the pineal gland. In the retina, the expression of both genes was characterized by a robust circadian rhythm of their transcript levels. In constant darkness, the rhythmic expression of retinal aanat2 persisted while the aanat1 rhythm disappeared; indicating that the former is controlled by a circadian clock and the latter is also light driven. In the light-entrainable clock-containing PAC-2 zebrafish cell line, both stably transfected aanat1 and aanat2 promoters exhibited a clock-controlled circadian rhythm, characteristic for an E-box-driven expression. Transient co-transfection experiments in NIH-3T3 cells revealed that the two, E-box- and PCE-containing, promoters are driven by the synergistic action of BMAL/CLOCK and orthehodenticle homeobox 5. This study has revealed a shared mechanism for the regulation of two related genes, yet describes their differential phases and photic responses which may be driven by other gene-specific regulatory mechanisms and tissue-specific transcription factor profiles.

Animals↗
PubMed1998

Effects of the endogenous clock and sleep time on melatonin, insulin, glucose and lipid metabolism.

This study was undertaken to determine whether the internal clock contributes to the hormone and metabolic responses following food, in an experiment designed to dissociate internal clock effects from other factors. Nine female subjects participated. They lived indoors for 31 days with normal time cues, including the natural light: darkness cycle. For 7 days they retired to bed from 0000 h to 0800 h. They then underwent a 26-h 'constant routine' (CR) starting at 0800 h, being seated awake in dim light with hourly 88 Kcal drinks. They then lived on an imposed 27-h day (18 h of wakefulness, 9 h allowed for sleep), for a total of 27 days. A second 26-h CR, starting at 2200 h, was completed. During each CR salivary melatonin and plasma glucose, triacylglycerol (TAG), non-essential fatty acids (NEFA), insulin, gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured hourly. Melatonin and body temperature data indicated no shift in the endogenous clock during the 27-h imposed schedule. Postprandial NEFA, GIP and GLP-1 showed no consistent effects. Glucose, TAG and insulin increased during the night in the first CR. There was a significant effect of both the endogenous clock and sleep for glucose and TAG, but not for insulin. These findings may be relevant to the known increased risk of cardiovascular disease amongst shift workers.

Adult↗
PubMed2003

The roles of vasoactive intestinal polypeptide in the mammalian circadian clock.

Biological oscillations with an endogenous period of near 24 h (circadian rhythms) are generated by the master circadian pacemaker or clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus. This clock is synchronised to recurring environmental signals conveyed by selective neural pathways. One of the main chemical constituents of SCN neurones is vasoactive intestinal polypeptide (VIP). Such neurones are retinorecipient and activated by light. Exogenous application of VIP resets the SCN circadian clock in a light-like manner, both in vivo and in vitro. These resetting actions appear to be mediated through the VPAC2 receptor (a type of receptor for VIP). Unexpectedly, genetically ablating expression of the VPAC2 receptor renders the circadian clock arrhythmic at the molecular, neurophysiological and behavioural levels. These findings indicate that this intrinsic neuropeptide acting through the VPAC2 receptor participates in both resetting to light and maintenance of ongoing rhythmicity of the SCN.

Animals↗
PubMed2002

Disorders of the circadian clock: etiology and possible therapeutic targets.

The mammalian circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus conveys 24-hr rhythmicity to sleep-wake cycles, temperature, locomotor activity and virtually all other behavioral and physiological processes. In order for these cycles to be adaptive, they must be synchronized, or entrained, to the 24-hr light/dark cycle produced by the rotation of the Earth. The timing of circadian variables relative to the light/dark cycle, i.e., the phase angle of entrainment, is influenced by intrinsic circadian clock properties that are to an extent genetically determined, and thus varies between individuals. In extreme cases (advanced or delayed sleep phase syndrome) or during shift work or jet lag, the phase angle of entrainment may be incompatible with work requirements or other social demands, resulting in negative consequences to health and productivity. This review describes the etiology of circadian disorders within the context of formal circadian clock properties and summarizes studies in humans and in other species which link specific genetic loci to circadian clock function and malfunction. The proteins encoded by these genetic loci play key roles in the intracellular feedback loop that generates circadian rhythms, and thus represent therapeutic targets for the treatment of both endogenous and exogenous circadian disorders.

Animals↗
PubMed2003

From light to genes: moving the hands of the circadian clock.

Mammalian circadian rhythms are generated by the hypothalamic suprachiasmatic nuclei and finely tuned to environmental periodicities by neurochemical responses to the light-dark cycle. Light reaches the clock through a direct retinohypothalamic tract, primarily through glutamatergic innervation, and its action is probably regulated by a variety of other neurotransmitters. A key second messenger in circadian photic entrainment is calcium, mobilized through membrane channels or intracellular reservoirs, which triggers the activation of several enzymes, including a calcium/calmodulin-dependent protein kinase and nitric oxide synthase. Other enzymes activated by light are mitogen-activated- and cGMP-dependent protein kinase; all of the above have been reported to be involved in the circadian responses to nocturnal light pulses. These mechanisms lead to expression of specific clock genes which eventually set the phase of the clock and of clock-controlled circadian rhythms.

Animals↗
PubMed2004

The mammalian circadian clock: a network of gene expression.

The circadian timing system provides a temporal structure across an organism to modulate and synchronize biological function. The mammalian circadian system is composed of many individual clocks. Circadian clocks are found in individual cells that have to be synchronized by a central pacemaker. This pacemaker can be viewed as a managing director who coordinates temporal physiology and behavior in the organism. In this review I will discuss the current understanding of the clock mechanism at the molecular level, how it adjusts to environmental changes and what the implications of a defect in the circadian clock are on mammalian physiology.

Animals↗
PubMed1990

Temporal discrimination in schizophrenic and affective disorders: evidence for a dopamine-dependent internal clock.

Performance in temporal discrimination of time intervals in the range of milliseconds was compared in 80 healthy subjects, 27 patients with schizophrenic disorders, 33 patients with major depression, 21 patients with dysthymic disorders. For schizophrenic patients as well as for patients with major depression, pronounced deficits in duration discrimination could be demonstrated as compared to the healthy control group (p less than .01). Patients with dysthymic disorders and schizophrenic patients differed significantly from the melancholic group (p less than .01 and p less than .05, respectively). The results are discussed on the basis of the assumption of an internal clock, implying that the clock rate is highest and therefore temporal resolution is best with healthy subjects. With psychiatric patients performance in temporal discrimination was impaired to a slowing down in clock rate and thus decreased temporal resolution. There is strong evidence that changes in clock rate depend on the effective level of dopamine. This leads to the conclusion that temporal discrimination thresholds may be seen as an indicator for deviations from the optimal level of dopaminergic activity in psychiatric patients. In addition, possible effects due to age and medication are discussed.

Analysis of Variance↗
PubMed2005

Circadian clock genes as modulators of sensitivity to genotoxic stress.

A broad variety of organisms display circadian rhythms (i.e., oscillations with 24-hr periodicities) in many aspects of their behavior, physiology and metabolism. These rhythms are under genetic control and are generated endogenously at the cellular level. In mammals, the core molecular mechanism of the oscillator consists of two transcriptional activators, CLOCK and BMAL1, and their transcriptional targets, CRYPTOCHROMES (CRYS) and PERIODS (PERS). The CRY and PER proteins function as negative regulators of CLOCK/BMAL1 activity, thus forming the major circadian autoregulatory feedback loop. It is believed that the circadian clock system regulates daily variations in output physiology and metabolism through periodic activation/repression of the set of clock-controlled genes that are involved in various metabolic pathways. Importantly, circadian-controlled pathways include those that determine in vivo responses to genotoxic stress. By using circadian mutant mice deficient in different components of the molecular clock system, we have established genetic models that correlate with the two opposite extremes of circadian cycle as reflected by the activity of the CLOCK/BMAL1 transactivation complex. Comparison of the in vivo responses of these mutants to the chemotherapeutic drug, cyclophosphamide (CY), has established a direct correlation between drug toxicity and the functional status of the CLOCK/BMAL1 transcriptional complex. We have also demonstrated that CLOCK/BMAL1 modulates sensitivity to drug-induced toxicity by controlling B cell responses to active CY metabolites. These results suggest that the sensitivity of cells to genotoxic stress induced by anticancer therapy may be modulated by CLOCK/BMAL1 transcriptional activity. Further elucidation of the molecular mechanisms of circadian control as well as identification of specific pharmacological modulators of CLOCK/BMAL1 activity are likely to lead to the development of new anti-cancer treatment schedules with increased therapeutic index and reduced morbidity.

Animals↗
PubMed2000

The circadian clock mutation alters sleep homeostasis in the mouse.

The onset and duration of sleep are thought to be primarily under the control of a homeostatic mechanism affected by previous periods of wake and sleep and a circadian timing mechanism that partitions wake and sleep into different portions of the day and night. The mouse Clock mutation induces pronounced changes in overall circadian organization. We sought to determine whether this genetic disruption of circadian timing would affect sleep homeostasis. The Clock mutation affected a number of sleep parameters during entrainment to a 12 hr light/dark (LD 12:12) cycle, when animals were free-running in constant darkness (DD), and during recovery from 6 hr of sleep deprivation in LD 12:12. In particular, in LD 12:12, heterozygous and homozygous Clock mutants slept, respectively, approximately 1 and approximately 2 hr less than wild-type mice, and they had 25 and 51% smaller increases in rapid eye movement (REM) sleep during 24 hr recovery, respectively, than wild-type mice. The effects of the mutation on sleep are not readily attributable to differential entrainment to LD 12:12 because the baseline sleep differences between genotypes were also present when animals were free-running in DD. These results indicate that genetic alterations of the circadian clock system and/or its regulatory genes are likely to have widespread effects on a variety of sleep and wake parameters, including the homeostatic regulation of sleep.

Animals↗
PubMed2000

Phase shifting the retinal circadian clock: xPer2 mRNA induction by light and dopamine.

A circadian clock is located in the retinal photoreceptors of the African clawed frog Xenopus laevis. These photoreceptor clocks are thought to govern a wide variety of output rhythms, including melatonin release and gene expression. Both light and dopamine phase shift the retinal clock in a phase-dependent manner. Two homologs of the Drosophila period gene have been cloned in Xenopus, and one of these (xPer2) is acutely regulated by light. Light and dopamine induce xPer2 mRNA in a similar manner. In addition, the increase of xPer2 mRNA in response to light and dopamine is the same at all times of day tested. In contrast, xPer1 mRNA exhibits circadian oscillations but is relatively insensitive to phase-shifting treatments of light or dopamine. Our data suggest that xPer2 functions as the molecular link between the light/dark cycle and the circadian clock.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1975

Deep hypothermia and its effect on the 24-hour clock of rats and hamsters.

Intensive hypothermia in rats and hamsters whose breathing and heartbeat had stopped for 1-4 hours was used as a setting in which to study the 24-hour biological clock. Pre- and post-hypothermia analyses depended on behavior wherein spontaneous running activity in revolving drums was used as a "hand" of the biological clock. Hypothermia had various effects. In some cases the clock was temporaily stopped, i.e., reset. In others it was simply slowed. Some clocks were both reset and slowed. Others ran without interruption even though breathing and heartbeat had stopped for 3-4 hours.

Animals↗