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At least 793 records · Page 44Linked to original sources
PubMed2004

Model based conjectures on mammalian clock controversies.

We explore some predictions of a previously developed detailed model of molecular timekeeping in mammals (Forger and Peskin, PNAS, 100:14806) in areas where our understanding of clock mechanisms are incomplete. It is conjectured that: (1) the clock's 24-h period depends on mRNA stability. (2) REV-ERBalpha suppresses and/or entrains rhythms in peripheral tissues by regulating CRY1 transcription. (3) CLK:BMAL1 oscillations are suppressed in the suprachiasmatic nuclei to enhance oscillations in other proteins. (4) PER2 is ineffective at causing phase advances because it is not induced by light during the late night. (5) The clock is a limit cycle oscillator that shows characteristics of the evening and morning oscillator model.

Animals↗
PubMed2004

Temperature compensation in circadian clock models.

Circadian clock of organisms has a free-running period that does not change much with ambient temperature. This property "temperature compensation" is studied when the rate of all reaction steps increase with temperature in the biochemical network generating the rhythm. The period becomes shorter when all the rate parameters are enhanced by the same factor. However, the period becomes longer as degradation rate of proteins and/or transcription rate of the clock gene increase (their elasticity is positive). This holds for a wide range of models, including N-variable model, and PER-TIM double oscillator model, provided that (1) branch reactions (e.g. degradation of proteins or mRNAs) are strongly saturated, and that (2) the cooperativity of transcription inhibition by nuclear proteins is not very large. A strong temperature sensitivity of degradation of PER proteins and/or temperature-sensitive alternative splicing of per gene, known for Drosophila, can be mechanisms for the temperature compensation of circadian clock.

Alternative Splicing↗
PubMed2004

Genetic dissection of drug effects in clinical practice: CLOCK gene and clozapine-induced diurnal sleepiness.

Psychotic patients treated with clozapine often experience persistent daytime sleepiness. This is a frequent side effect of clozapine that may reduce patient compliance. We hypothesized that clozapine might interfere with the circadian rhythms regulated by the biological clock. In 171 patients with major psychosis, we investigated the association between hypersomnolence during clozapine therapy and a CLOCK gene polymorphism (3111 T/C substitution). Forty-six patients showed persistent daytime sleepiness and were classified as "sleepy". "Sleepy" patients were significantly more likely to have a mutated allele compared to both "non sleepy" patients and healthy subjects (chi2 = 20.36, d.f. = 1, P = 0.000007, and chi2 = 13.91, d.f. = 1, P = 0.0002, respectively). We conclude that an interaction between clozapine and the CLOCK gene polymorphism 3111 T/C substitution could explain persistent daytime sleepiness in a significant proportion of patients treated with clozapine.

Adult↗
PubMed2006

Rhythmic post-transcriptional regulation of the circadian clock protein mPER2 in mammalian cells: a real-time analysis.

Post-transcriptional/translational mechanisms regulate the circadian clock system of many organisms, including mammals. The level of the essential clock protein mPER2 daily oscillates in peripheral cells as well as in neurons of the master oscillator in the suprachiasmatic nucleus (SCN). Post-translational modifications of mPER2, such as phosphorylation and ubiquitination, are likely involved in the regulation of its stability and intracellular accumulation rhythms, which in turn create an approximately 2-4 h delay from the rhythm of mPer2 mRNA. However, there are no direct evidences linking the above biochemical processes to the generation of the mPER2 protein cycle itself. Here, we show that multiple circadian waves of bioluminescence are detectable in cells constitutively expressing an mPer2-luciferase fusion mRNA. This suggests that a post-transcriptional/translational mechanism itself is capable of generating the circadian mPER2 accumulation cycle, and thus this type of regulation may function in the circadian clock system in mammals.

Animals↗
PubMed2004

A functional genomics strategy reveals Rora as a component of the mammalian circadian clock.

The mammalian circadian clock plays an integral role in timing rhythmic physiology and behavior, such as locomotor activity, with anticipated daily environmental changes. The master oscillator resides within the suprachiasmatic nucleus (SCN), which can maintain circadian rhythms in the absence of synchronizing light input. Here, we describe a genomics-based approach to identify circadian activators of Bmal1, itself a key transcriptional activator that is necessary for core oscillator function. Using cell-based functional assays, as well as behavioral and molecular analyses, we identified Rora as an activator of Bmal1 transcription within the SCN. Rora is required for normal Bmal1 expression and consolidation of daily locomotor activity and is regulated by the core clock in the SCN. These results suggest that opposing activities of the orphan nuclear receptors Rora and Rev-erb alpha, which represses Bmal1 expression, are important in the maintenance of circadian clock function.

ARNTL Transcription Factors↗
PubMed2006

Rethinking the biological clock: eleventh-hour moms, miracle moms and meanings of age-related infertility.

Over the past generation, aging and female reproduction have been lodged within the gendered and gendering debates regarding women's involvement in the workforce and demographic shifts toward delayed parenting that culminate in discourses on the "biological clock". Technological solutions to the biological clock, specifically in vitro fertilization, have led to clinical attempts to assess "ovarian reserve", or qualitative and quantitative changes in the ovary that correlate with aging and with successful infertility treatment. Rupturing the longstanding historical connections between menstruation and female reproductive capacity by specifically focusing on the aging of a woman's eggs, the clinical designation of "diminished ovarian reserve" has come to imply that a woman has "old eggs". This is associated in practitioners' and patients' minds with the eclipse of a woman's reproductive potential and with hidden harbingers of menopause. In an ethnographic interview study of 79 couples in the US who conceived after using donor oocytes, we found that women voiced two different narratives that described their experience and attitudes when confronted with an apparent age-related decline in their fertility. The "eleventh-hour mom" narrative was voiced by women who initially tried to become pregnant with their own eggs and turned to donated oocytes as a second-choice option, whereas the "miracle mom" narrative was expressed by women who were generally older, some of whom had entered infertility treatment hoping to conceive with their own eggs, but some who knew from the outset that it was not going to be possible. Through their narratives women not only embodied and made meaningful "diminished ovarian reserve" in varying ways that connect with cultural, social, structural/organizational, symbolic and physical aspects of aging, they reproduced the socio-biological project of the biological clock, but rooted this social project in the metaphor of "old eggs" rather than menopause.

Adult↗
PubMed2006

A sense of time: how molecular clocks organize metabolism.

The discovery of an internal temporal clockwork that coordinates behavior and metabolism according to the rising and setting of the sun was first revealed in flies and plants. However, in the past decade, a molecular transcription-translation feedback loop with similar properties has also been identified in mammals. In mammals, this transcriptional oscillator programs 24-hour cycles in sleep, activity and feeding within the master pacemaker neurons of the suprachiasmatic nucleus of the hypothalamus. More recent studies have shown that the core transcription mechanism is also present in other locations within the brain, in addition to many peripheral tissues. Processes ranging from glucose transport to gluconeogenesis, lipolysis, adipogenesis and mitochondrial oxidative phosphorylation are controlled through overlapping transcription networks that are tied to the clock and are thus time sensitive. Because disruption of tissue timing occurs when food intake, activity and sleep are altered, understanding how these many tissue clocks are synchronized to tick at the same time each day, and determining how each tissue 'senses time' set by these molecular clocks might open new insight into human disease, including disorders of sleep, circadian disruption, diabetes and obesity.

Animals↗
PubMed2005

Gene duplication and complex circadian clocks in mammals.

The circadian clock arose early in the evolution of life to enable organisms to adapt to the cycle of day and night. Recently, the extent and importance of circadian regulation of behaviour and physiology has come to be more fully realized. Core molecular cogs of circadian oscillators appear to have been largely conserved between such diverse organisms as Drosophila melanogaster and mammals. However, gene duplication events have produced multiple copies of many clock genes in mammals. Recent studies suggest that genome duplication has lead to increased circadian complexity and local tissue regulation. This has important implications for temporal regulation of behaviour via multiple clocks in the central nervous system, and also extends to the local physiology of major body organs and tissues.

Animals↗
PubMed2006

Clock genes: influencing and being influenced by psychoactive drugs.

Although clock genes are the hallmark of circadian rhythms, they are also currently considered as transcription factors that have a prominent role in the pharmacology of the CNS. The expression of these transcription factors in the mammalian brain is not only intrinsically rhythmic but is also modulated by external inputs and hormones. An altered expression of clock genes, as evidenced in transgenic mice, has a profound influence on the behavioral effects of psychoactive drugs. Focusing on clock genes expressed in the brain might lead to the discovery of novel drug-target pathways.

ARNTL Transcription Factors↗
PubMed2006

A clock and wavefront mechanism for somite formation.

Somitogenesis, the sequential formation of a periodic pattern along the antero-posterior axis of vertebrate embryos, is one of the most obvious examples of the segmental patterning processes that take place during embryogenesis and also one of the major unresolved events in developmental biology. In this article, we develop a mathematical formulation of a new version of the Clock and Wavefront model proposed by Pourquié and co-workers (Dubrulle, J., McGrew, M.J., Pourquié, O., 2001. FGF signalling controls somite boundary position and regulates segmentation clock control of spatiotemporal Hox gene activation. Cell 106, 219-232). Dynamic expression of FGF8 in the presomitic mesoderm constitutes the wavefront of determination which sweeps along the body axis interacting as it moves with the segmentation clock to gate cells into somites. We also show that the model can mimic the anomalies formed when progression of the wavefront is disturbed and make some experimental predictions that can be used to test the hypotheses underlying the model.

Animals↗
PubMed2002

MDMA alters the response of the circadian clock to a photic and non-photic stimulus.

3,4-Methylenedioxymethamphetamine (MDMA or 'Ecstasy') is a widely used recreational drug that damages serotonin 5-HT neurons in animals and possibly humans. Published literature has shown that the serotonergic system is involved in photic and non-photic phase shifting of the circadian clock, which is located in the suprachiasmatic nuclei. Despite the dense innervation of the circadian system by 5-HT and the known selective neurotoxicity of MDMA, little is known about the effects of MDMA on the circadian oscillator. This study investigated whether repeated exposure to the serotonin neurotoxin MDMA alters the behavioural response of the Syrian hamster to phase shift to the serotonin 5-HT1A/7 receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT). This agonist was administered under an Aschoff Type I (CT8) and Aschoff Type II (ZT8) paradigm (5 mg/kg) and was given before and after treatment with MDMA (10, 15 and 20 mg/kg administered on successive days). Pre-treatment with MDMA significantly attenuated phase shifts to 8-OH-DPAT. We also tested the ability of the clock to phase shift to a photic stimulus after treatment with MDMA. A 15-min light pulse (mean lux 125 at CT14 or ZT14) was administered before and after treatment with MDMA. Phase shifts to a photic stimulus were significantly attenuated by pre-treatment with MDMA. Our study demonstrates that repeated exposure to MDMA may alter the ability of the circadian clock to phase shift to a photic and non-photic stimulus in the hamster. Disruption of circadian function has been linked with a variety of clinical conditions such as sleep disorders, mood, concentration difficulties and depression, consequently outlining the potential dangers of long-term ecstasy use.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

A molecular clock involved in somite segmentation.

Somites are transient embryonic structures that are formed from the unsegmented presomitic mesoderm (PSM) in a highly regulated process called somitogenesis. Somite, formation can be considered as the result of several sequential processes: generation of a basic metameric pattern, specification of the antero-posterior identity of each somite, and, finally, formation of the somitic border. Evidence for the existence of a molecular clock or oscillator linked to somitogenesis has been provided by the discovery of the rhythmic and dynamic expression in the PSM of c-hairy1 and lunatic fringe, two genes potentially related to the Notch signaling pathway. These oscillating expression patterns suggest that an important role of the molecular clock could reside in the temporal control of periodic Notch activation, ultimately resulting in the regular array of the somites. We discuss both the importance of the Notch signaling pathway in the molecular events of somitogenesis and its relationship with the molecular clock, and, finally, in that context we review a number of other genes known to play a role in somitogenesis.

Animals↗
PubMed2006

Kinase and phosphatase: the cog and spring of the circadian clock.

Reversible phosphorylation is an important regulatory mechanism for many biological processes in eukaryotic organisms. The phosphorylation state of a protein is controlled dynamically by both protein kinases and phosphatases. Phosphorylation of circadian clock proteins is an essential posttranscriptional mechanism in the regulation of circadian clocks, and several protein kinases and phosphatases have been shown to regulate key clock components in eukaryotic systems, including Arabidopsis, Neurospora, Drosophila, and mice. In this review, recent progress in the characterization of protein kinases and phosphatases involved in circadian rhythms is summarized. The protein kinase CK2 has been proposed as an evolutionary link between the divergent circadian systems of plants, animals, and fungi. The roles of CK2 in this process are discussed here in detail.

Animals↗
PubMed2005

Oligodeoxynucleotide methods for analyzing the circadian clock in the suprachiasmatic nucleus.

The recent identification of specific genes responsible for the generation of endogenous circadian rhythmicity in the suprachiasmatic nucleus presents a new level of investigation into endogenous rhythmicity and mechanisms of synchronization of this circadian clock with the environmental light?dark cycle. This article describes techniques that employ antisense and decoy oligodeoxynucleotides (ODN) to determine the roles of specific molecular substrates both in endogenous rhythmicity and in regulating the effects of light on the mammalian circadian clock. Application of antisense ODN technology has revealed a role for timeless (Tim) in the core clock mechanism and established that induction of period1 (Per1) is required for light responsiveness. Likewise, a decoy ODN designed to sequester activated CREB protein definitively demonstrated a requirement for CRE-mediated transcription in light signaling. Experiments designed with these molecular tools offer new insights on the interaction of cellular processes and signaling with the molecular clockworks.

Animals↗
PubMed2005

Membranes, ions, and clocks: testing the Njus-Sulzman-Hastings model of the circadian oscillator.

Current circadian clock models based on interlocking autoregulatory transcriptional?translational negative feedback loops have arisen out of an explosion of molecular genetic data obtained over the last decade (for review, see Stanewsky, 2003; Young and Kay, 2001). An earlier model of circadian oscillation was based on feedback interactions between membrane ion transport systems and ion concentration gradients (Njus et al., 1974, 1976). This membrane model was posited as a more plausible alternative at the time to the even earlier "chronon" model, which was based on autoregulatory genetic feedback loops (Ehret and Trucco, 1967). The membrane model has been tested in a number of experimental systems by pharmacologically manipulating either ionic gradients across the plasma membrane or ion transport systems, but with inconsistent results. In the meantime, the scope and explanatory power of the genetic models overshadowed inquiries into the role of membrane ion fluxes in clock function. However, several recently developed techniques described in this article have provided a new glimpse into the essential role that membrane ion fluxes play in the mechanism of the core circadian oscillator and indicate that a complete understanding of the clock must include both genetic and membrane-based feedback loops.

Action Potentials↗
PubMed1998

A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless.

We report the identification, characterization, and cloning of a novel Drosophila circadian rhythm gene, dClock. The mutant, initially called Jrk, manifests dominant effects: heterozygous flies have a period alteration and half are arrhythmic, while homozygous flies are uniformly arrhythmic. Furthermore, these flies express low levels of the two clock proteins, PERIOD (PER) and TIMELESS (TIM), due to low per and tim transcription. Mapping and cloning of the Jrk gene indicates that it encodes the Drosophila homolog of mouse Clock. The mutant phenotype results from a premature stop codon that eliminates much of the putative activation domain of this bHLH-PAS transcription factor, thus explaining the dominant features of Jrk. The remarkable sequence conservation strongly supports common clock components present in the common ancestor of Drosophila and mammals.

Animals↗
PubMed1998

Constitutive expression of the CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) gene disrupts circadian rhythms and suppresses its own expression.

The CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) gene encodes a MYB-related transcription factor involved in the phytochrome induction of a light-harvesting chlorophyll a/b-protein (Lhcb) gene. Expression of the CCA1 gene is transiently induced by phytochrome and oscillates with a circadian rhythm. Constitutive expression of CCA1 protein in transgenic plants abolished the circadian rhythm of several genes with dramatically different phases. These plants also had longer hypocotyls and delayed flowering, developmental processes regulated by light and the circadian clock. Furthermore, the expression of both endogenous CCA1 and the related LHY gene was suppressed. Our results suggest that CCA1 is a part of a feedback loop that is closely associated with the circadian clock in Arabidopsis.

Arabidopsis↗
PubMed2002

Electrical silencing of Drosophila pacemaker neurons stops the free-running circadian clock.

Electrical silencing of Drosophila circadian pacemaker neurons through targeted expression of K+ channels causes severe deficits in free-running circadian locomotor rhythmicity in complete darkness. Pacemaker electrical silencing also stops the free-running oscillation of PERIOD (PER) and TIMELESS (TIM) proteins that constitutes the core of the cell-autonomous molecular clock. In contrast, electrical silencing fails to abolish PER and TIM oscillation in light-dark cycles, although it does impair rhythmic behavior. On the basis of these findings, we propose that electrical activity is an essential element of the free-running molecular clock of pacemaker neurons along with the transcription factors and regulatory enzymes that have been previously identified as required for clock function.

Action Potentials↗