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PubMed2002

The mammalian retina as a clock.

Many physiological, cellular, and biochemical parameters in the retina of vertebrates show daily rhythms that, in many cases, also persist under constant conditions. This demonstrates that they are driven by a circadian pacemaker. The presence of an autonomous circadian clock in the retina of vertebrates was first demonstrated in Xenopus laevis and then, several years later, in mammals. In X. laevis and in chicken, the retinal circadian pacemaker has been localized in the photoreceptor layer, whereas in mammals, such information is not yet available. Recent advances in molecular techniques have led to the identification of a group of genes that are believed to constitute the molecular core of the circadian clock. These genes are expressed in the retina, although with a slightly different 24-h profile from that observed in the central circadian pacemaker. This result suggests that some difference (at the molecular level) may exist between the retinal clock and the clock located in the suprachiasmatic nuclei of hypothalamus. The present review will focus on the current knowledge of the retinal rhythmicity and the mechanisms responsible for its control.

Animals↗
PubMed1976

Characteristics of a neural clock regulating perception and psychomotor performance in man.

A biological clock regulating some psychomotor aspects of perception has been adduced from the results of the repetitive administration of a maximal speed tapping test of 15 sec per hand per min for a total of 20 min. 412 longitudinal timed tests from 8 healthy control subjects, 4 physically healthy and 6 brain damaged psychiatric patients formed the basis for the investigation of the properties of this clock. It was found that this perceptual clock is endogenous, self-sustaining and innate. Its free-running oscillations are independent of psychic state, emotions and affect. They are, however, dependent upon the subject's neural integrity and their phase may be influenced by an orientating reflex. Timing is precise but the preceding phase may influence a succeeding one. Despite the muscular activity of the task the clock is relatively independent of body temperature. It is also immune to most psychoactive drugs.

Adult↗
PubMed1995

Period protein from the giant silkmoth Antheraea pernyi functions as a circadian clock element in Drosophila melanogaster.

Homologs of the Drosophila clock gene per have recently been cloned in Lepidopteran and Blattarian insect species. To assess the extent to which clock mechanisms are conserved among phylogenetically distant species, we determined whether PER protein from the silkmoth Antheraea pernyi can function in the Drosophila circadian timing system. When expressed in transgenic Drosophila, the silkmoth PER protein is detected in the expected neural cell types, with diurnal changes in abundance that are similar to those observed in wild-type fruitflies. Behavioral analysis demonstrates that the silkmoth protein can serve as a molecular element of the Drosophila clock system; expression of the protein shortens circadian period in a dose-dependent manner and restores pacemaker functions to arrhythmic per0 mutants. This comparative study also suggests that the involvement of PER in different aspects of circadian timing, such as period determination, strength of rhythmicity, and clock out-put, requires distinct molecular interactions.

Animals↗
PubMed2005

Overlapping and distinct roles of PRR7 and PRR9 in the Arabidopsis circadian clock.

The core mechanism of the circadian oscillators described to date rely on transcriptional negative feedback loops with a delay between the negative and the positive components . In plants, the first suggested regulatory loop involves the transcription factors CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY) and the pseudo-response regulator TIMING OF CAB EXPRESSION 1 (TOC1/PRR1). TOC1 is a member of the Arabidopsis circadian-regulated PRR gene family . Analysis of single and double mutants in PRR7 and PRR9 indicates that these morning-expressed genes play a dual role in the circadian clock, being involved in the transmission of light signals to the clock and in the regulation of the central oscillator. Furthermore, CCA1 and LHY had a positive effect on PRR7 and PRR9 expression levels, indicating that they might form part of an additional regulatory feedback loop. We propose that the Arabidopsis circadian oscillator is composed of several interlocking positive and negative feedback loops, a feature of clock regulation that appears broadly conserved between plants, fungi, and animals.

Arabidopsis↗
PubMed2005

The biological clock of an hematophagous insect: locomotor activity rhythms, circadian expression and downregulation after a blood meal.

Despite the importance of circadian rhythms in vector-borne disease transmission, very little is known about its molecular control in hematophagous insect vectors. In Drosophila melanogaster, a negative feedback loop of gene expression has been shown to contribute to the clock mechanism. Here, we describe some features of the circadian clock of the sandfly Lutzomyia longipalpis, a vector of visceral leishmaniasis. Compared to D. melanogaster, sandfly period and timeless, two negative elements of the feedback loop, show similar peaks of mRNA abundance. On the other hand, the expression of Clock (a positive transcription factor) differs between the two species, raising the possibility that the different phases of Clock expression could be associated with the observed differences in circadian activity rhythms. In addition, we show a reduction in locomotor activity after a blood meal, which is correlated with downregulation of period and timeless expression levels. Our results suggest that the circadian pacemaker and its control over the activity rhythms in this hematophagous insect are modulated by blood intake.

Animals↗
PubMed2005

How similar are daily and seasonal biological clocks?

Daily and seasonal timing systems in insects have usually been supposed to share similar mechanisms, because both rely in large measure on information from the daily light-dark cycle: daily clocks can ensure that activity coincides with the appropriate time of day, and seasonal time is indicated most reliably by daylength. However, several lines of evidence suggest that the systems are different. For example, receptor features, photosensitive pigments, clocks, and the effectors that mediate responses to information derived from the clock may have different daily, seasonal and general functions and properties, and several different systems are known. There are many different additional elements in the seasonal response. Therefore, these responses may not rely on similar timing mechanisms, despite the long-standing belief that the seasonal clock has circadian components. Such a difference would be consistent with the fact that temporal responses serve a very wide range of purposes, meeting many different ecological needs on different time frames. Consequently, understanding the seasonal relevance of the photoperiodic responses is more important than revealing any possible involvement with circadian systems.

Animals↗
PubMed2004

Structure of the N-terminal domain of the circadian clock-associated histidine kinase SasA.

Circadian oscillators are endogenous biological systems that generate the approximately 24 hour temporal pattern of biological processes and confer a reproductive fitness advantage to their hosts. The cyanobacterial clock is the simplest known and the only clock system for which structural information for core component proteins, in this case KaiA, KaiB and KaiC, is available. SasA, a clock-associated histidine kinase, is necessary for robustness of the circadian rhythm of gene expression and implicated in clock output. The N-terminal domain of SasA (N-SasA) interacts directly with KaiC and likely functions as the sensory domain controlling the SasA histidine kinase activity. N-SasA and KaiB share significant sequence similarity and, thus, it has been proposed that they would be structurally similar and may even compete for KaiC binding. Here, we report the NMR structure of N-SasA and show it to be different from that of KaiB. The structural comparisons provide no clear details to suggest competition of SasA and KaiB for KaiC binding. N-SasA adopts a canonical thioredoxin fold but lacks the catalytic cysteine residues. A patch of conserved, solvent-exposed residues is found near the canonical thioredoxin active site. We suggest that this surface is used by N-SasA for protein-protein interactions. Our analysis suggests that the structural differences between N-SasA and KaiB are the result of only a few critical amino acid substitutions.

Amino Acid Sequence↗
PubMed2004

Periodic dip of lipidperoxidation in humans: a redox signal to synchronize peripheral circadian clocks?

The output generated by the endogenous circadian clock to control circadian functions and temporal organization in metazoans is unknown. Redox state perturbations generated by reactive oxygen species (ROS) and antioxidants are known to influence the expression of a number of genes and signal transduction pathways. Evidence has been recently provided that the reduced redox cofactors NAD and NADP both regulate clock gene activity in the suprachiasmatic nucleus (SCN) and are induced by it. Significant periodic variations of lipidperoxidation in human blood with a dip at 04.00 h have been previously reported. Such variations could be expected to alter the cellular redox state, thus possibly functioning as periodic redox signals from the master clock. To verify the existence of the mentioned variations the serum levels of malondialdehyde (MDA), a marker of lipidperoxidation, were monitored by High-Performance Liquid Chromatography in 39 healthy subjects at 3-h intervals over a 24-h period. Throughout the test period, only biological noise could be detected in all test persons. However, the normalized MDA levels at 03.00 h were significantly lower (p < 0.05 to < 0.00005) in 38 (97%) of the cases and showed a significantly lower standard deviation (p < 0.004) than at any of the other 3-h intervals, indicating a periodic dip of lipidperoxidation (PDL) in diurnal active subjects. We hypothesize that the PDL, on the basis of its time of appearance, its frequency and its potential influence on cellular redox state, represents a periodic systemic redox output of the SCN, in terms of a relatively short and sudden interruption of the daily oxidative noise. According to recent research, it could be the result of redox alterations induced by the SCN activity and at the same time the pathway by which the master clock resets and synchronizes peripheral oscillators to the light/dark cycle. Additionally, the antioxidative function of the pineal gland activity postulated elsewhere could play a part in generating the described phenomenon. The PDL could be useful as a circadian phase marker in research dealing with treatment of jet lag and other sleep disorders.

Adolescent↗
PubMed2004

Dexras1 potentiates photic and suppresses nonphotic responses of the circadian clock.

Circadian rhythms of physiology and behavior are generated by biological clocks that are synchronized to the cyclic environment by photic or nonphotic cues. The interactions and integration of various entrainment pathways to the clock are poorly understood. Here, we show that the Ras-like G protein Dexras1 is a critical modulator of the responsiveness of the master clock to photic and nonphotic inputs. Genetic deletion of Dexras1 reduces photic entrainment by eliminating a pertussis-sensitive circadian response to NMDA. Mechanistically, Dexras1 couples NMDA and light input to Gi/o and ERK activation. In addition, the mutation greatly potentiates nonphotic responses to neuropeptide Y and unmasks a nonphotic response to arousal. Thus, Dexras1 modulates the responses of the master clock to photic and nonphotic stimuli in opposite directions. These results identify a signaling molecule that serves as a differential modulator of the gated photic and nonphotic input pathways to the circadian timekeeping system.

Animals↗
PubMed2005

Connecting the navigational clock to sun compass input in monarch butterfly brain.

Migratory monarch butterflies (Danaus plexippus) use a time-compensated sun compass to navigate to their overwintering grounds in Mexico. Although polarized light is one of the celestial cues used for orientation, the spectral content (color) of that light has not been fully explored. We cloned the cDNAs of three visual pigment-encoding opsins (ultraviolet [UV], blue, and long wavelength) and found that all three are expressed uniformly in main retina. The photoreceptors of the polarization-specialized dorsal rim area, on the other hand, are monochromatic for the UV opsin. Behavioral studies support the importance of polarized UV light for flight orientation. Next, we used clock protein expression patterns to identify the location of a circadian clock in the dorsolateral protocerebrum of butterfly brain. To provide a link between the clock and the sun compass, we identified a CRYPTOCHROME-staining neural pathway that likely connects the circadian clock to polarized light input entering brain.

Animal Migration↗
PubMed2006

CLOCK leaves its mark on histones.

Transcriptional regulation of circadian rhythms in mammals involves a negative-feedback loop whereby a CLOCK-BMAL1 complex activates transcription of the genes encoding the proteins PER1 (Period 1), PER2, CRY1 (Cryptochrome 1) and CRY2, which feed back to inhibit the activity of CLOCK-BMAL1. It is becoming evident that chromatin remodeling has a crucial role in the transcriptional regulation of genes governing circadian rhythms. This is highlighted in a recent report that shows that CLOCK has histone acetyltransferase activity, thus, demonstrating that molecular components of the biological clock can themselves catalyze chromatin modifications.

ARNTL Transcription Factors↗
PubMed2001

Circadian expression of clock genes in human oral mucosa and skin: association with specific cell-cycle phases.

We studied the relative RNA expression of clock genes throughout one 24-hour period in biopsies obtained from the oral mucosa and skin from eight healthy diurnally active male study participants. We found that the human clock genes hClock, hTim, hPer1, hCry1, and hBmal1 are expressed in oral mucosa and skin, with a circadian profile consistent with that found in the suprachiasmatic nuclei and the peripheral tissues of rodents. hPer1, hCry1, and hBmal1 have a rhythmic expression, peaking early in the morning, in late afternoon, and at night, respectively, whereas hClock and hTim are not rhythmic. This is the first human study to show a circadian profile of expression for all five clock genes as documented in rodents, suggesting their functional importance in man. In concurrent oral mucosa biopsies, thymidylate synthase enzyme activity, a marker for DNA synthesis, had a circadian variation with peak activity in early afternoon, coinciding with the timing of S phase in our previous study on cell-cycle timing in human oral mucosa. The major peak in hPer1 expression occurs at the same time of day as the peak in G(1) phase in oral mucosa, suggesting a possible link between the circadian clock and the mammalian cell cycle.

ARNTL Transcription Factors↗
PubMed2003

MAP kinase-dependent induction of clock gene expression by alpha 1-adrenergic receptor activation.

While peripheral oscillators can be reset by humoral factors such as glucocorticoid hormones, indirect neural communications involving sympathetic and parasympathetic neurons from the suprachiasmatic nucleus to various peripheral tissues suggest that autonomic nerve innervations also function in the resetting and synchronization of peripheral tissues. To study the role of sympathetic adrenergic signaling on clock gene expression, we constructed NIH3T3 cells that stably expressed each of three alpha(1)-adrenergic receptor subtypes (alpha(1A), alpha(1B) and alpha(1D)). We found that noradrenaline transiently induced the expression of mPer1, mPer2, and mE4bp4 1-2 h after alpha(1)-receptor activation. The extent and time course of clock gene mRNA induction by noradrenaline or the alpha(1)-receptor agonist phenylephrine (PE) was similar to that seen by 50% horse serum shock. Clock gene mRNA induction by PE was inhibited by U0126, a MEK inhibitor, suggesting involvement of the mitogen-activated protein kinase signaling pathway. We also found that both mPer1 and mPer2 mRNAs were induced in the mouse liver 60 min after PE injection. These results suggest that although humoral factors are important for entrainment of the peripheral clock, the autonomic nervous system may also be involved in the process.

3T3 Cells↗
PubMed2003

Experimental evidence for a non-clock role of the circadian system in spider mite photoperiodism.

In the spider mite Tetranychus urticae photoperiodic time measurement proceeds accurately in orange-red light of 580 nm and above in light/dark cycles with a period length of 20 h but not in 'natural' cycles with a period length of 24 h. To explain these results it is hypothesized that the photoperiodic clock in the spider mite is sensitive to orange-red light, but the Nanda-Hamner rhythm (a circadian rhythm with a free-running period tau of 20 h involved in the photoperiodic response) is not and consequently free runs in orange-red light. To test this hypothesis a zeitgeber was sought that could entrain the Nanda-Hamner rhythm to a 24-h cycle without inducing diapause itself, in order to manipulate the rhythm independently from the orange-red sensitive photoperiodic clock. A suitable zeitgeber was found to be a thermoperiod with a 12-h warm phase and a 12-h cold phase. Combining the thermoperiod with the long-night orange-red light/dark regime, both with a cycle length of 24 h, resulted in a high diapause incidence, although neither regime was capable of inducing diapause on its own. The conclusion is that the Nanda-Hamner rhythm is necessary for the realization of the photoperiodic response, but is not part of the photoperiodic clock, because photoperiodic time measurement takes place in orange-red light whereas the rhythm is not able to 'see' the orange-red light. It is speculated that the Nanda-Hamner rhythm is involved in the timely synthesis of a substrate for the photoperiodic clock in the spider mite.

Animals↗
PubMed1997

Thermally regulated translational control of FRQ mediates aspects of temperature responses in the neurospora circadian clock.

Two forms of FRQ, a central component of the Neurospora circadian clock, arise through alternative in-frame initiation of translation. Either form alone suffices for a functional clock at some temperatures, but both are always necessary for robust rhythmicity. Temperature regulates the ratio of FRQ forms by favoring different initiation codons at different temperatures; when either initiation codon is eliminated, the temperature range permissive for rhythmicity is demonstrably reduced. This temperature-influenced choice of translation-initiation site represents a novel adaptive mechanism that extends the physiological temperature range over which clocks function. Additionally, a temperature-dependent threshold level of FRQ is required to establish the feedback loop comprising the oscillator. These data may explain how temperature limits permissive for rhythmicity are established, thus providing a molecular understanding for a basic characteristic of circadian clocks.

Biological Clocks↗
PubMed2001

Chimera analysis of the Clock mutation in mice shows that complex cellular integration determines circadian behavior.

The Clock mutation lengthens periodicity and reduces amplitude of circadian rhythms in mice. The effects of Clock are cell intrinsic and can be observed at the level of single neurons in the suprachiasmatic nucleus. To address how cells of contrasting genotype functionally interact in vivo to control circadian behavior, we have analyzed a series of Clock mutant mouse aggregation chimeras. Circadian behavior in Clock/Clock <--> wild-type chimeric individuals was determined by the proportion of mutant versus normal cells. Significantly, a number of intermediate phenotypes, including Clock/+ phenocopies and novel combinations of the parental behavioral characteristics, were seen in balanced chimeras. Multivariate statistical techniques were used to quantitatively analyze relationships among circadian period, amplitude, and suprachiasmatic nucleus composition. Together, our results demonstrate that complex integration of cellular phenotypes determines the generation and expression of coherent circadian rhythms at the organismal level.

Animals↗
PubMed2002

Phenotypic rescue of a peripheral clock genetic defect via SCN hierarchical dominance.

The mammalian circadian system contains both central and peripheral oscillators. To understand the communication pathways between them, we have studied the rhythmic behavior of mouse embryo fibroblasts (MEFs) surgically implanted in mice of different genotypes. MEFs from Per1(-/-) mice have a much shorter period in culture than do tissues in the intact animal. When implanted back into mice, however, the Per1(-/-) MEF take on the rhythmic characteristics of the host. A functioning clock is required for oscillations in the target tissues, as arrhythmic clock(c/c) MEFs remain arrhythmic in implants. These results demonstrate that SCN hierarchical dominance can compensate for severe intrinsic genetic defects in peripheral clocks, but cannot induce rhythmicity in clock-defective tissues.

Animals↗
PubMed2000

Molecular clock genes in man and lower animals: possible implications for circadian abnormalities in depression.

This paper reviews the recent discovery of clock genes that provide the mechanism for the regulation of circadian and seasonal rhythms in lower organisms and in humans and relates these clock genes to the circadian abnormalities in depression. (1) A subgroup of depressed patients have documented circadian abnormalities in mood, sleep, temperature and neuroendocrine secretion; (2) It is also suggested that seasonal affective disorder (SAD) patients may show an abnormality in their ability to shift their daily circadian rhythms in response to seasonal light changes; (3) The dramatic improvements in some depressions in response to three treatment modalities which manipulate circadian rhythms suggest that circadian abnormalities reported in patients may constitute a core component of the pathophysiology in depression; (4) Mutations in clock genes have been discovered that accelerate or delay circadian cycles; (5) It is hypothesized that 24-hour rhythm abnormalities in major depression and SAD may be due to altered clock genes.

Animals↗