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PubMed2005

PSEUDO-RESPONSE REGULATOR 7 and 9 are partially redundant genes essential for the temperature responsiveness of the Arabidopsis circadian clock.

Environmental time cues, such as photocycles (light/dark) and thermocycles (warm/cold), synchronize (entrain) endogenous biological clocks to local time. Although much is known about entrainment of the Arabidopsis thaliana clock to photocycles, the determinants of thermoperception and entrainment to thermocycles are not known. The Arabidopsis PSEUDO-RESPONSE REGULATOR (PRR) genes, including the clock component TIMING OF CAB EXPRESSION 1/PRR1, are related to bacterial, fungal, and plant response regulators but lack the conserved Asp that is normally phosphorylated by an upstream sensory kinase. Here, we show that two PRR family members, PRR7 and PRR9, are partially redundant; single prr7-3 or prr9-1 mutants exhibit modest period lengthening, but the prr7-3 prr9-1 double mutant shows dramatic and more than additive period lengthening in the light and becomes arrhythmic in constant darkness. The prr7-3 prr9-1 mutant fails both to maintain an oscillation after entrainment to thermocycles and to reset its clock in response to cold pulses and thus represents an important mutant strongly affected in temperature entrainment in higher plants. We conclude that PRR7 and PRR9 are critical components of a temperature-sensitive circadian system. PRR7 and PRR9 could function in temperature and light input pathways or they could represent elements of an oscillator necessary for the clock to respond to temperature signals.

Alleles↗
PubMed2003

The days and nights of cancer cells.

Biological clocks are intrinsic time-keeping systems that regulate behavior and physiological functions in most living organisms. Recent works in this area have addressed possible molecular links between the endogenous circadian clock and cell cycle regulation. In this review, by addressing how circadian clocks can interfere with the cell cycle and how the disruption of the circadian rhythm may cause defects in regulation of cell proliferation, we highlight this potential connection between circadian rhythm and cell cycle. We also discuss how the acquisition of recent data in circadian clock mechanism may help chronotherapy, which takes into account the biological time to improve cancer treatments, and may open new therapeutic avenues for treating circadian-related diseases.

Animals↗
PubMed2002

The p42/44 mitogen-activated protein kinase pathway couples photic input to circadian clock entrainment.

In mammals, the suprachiasmatic nuclei (SCN) of the hypothalamus function as the major biological clock. SCN-dependent rhythms of physiology and behavior are regulated by changes in the environmental light cycle. Currently, the second messenger signaling events that couple photic input to clock entrainment have yet to be well characterized. Recent work has revealed that photic stimulation during the night triggers rapid activation of the p42/44 mitogen activated protein kinase (MAPK) pathway in the SCN. The MAPK signal transduction pathway is a potent regulator of numerous classes of transcription factors and has been shown to play a role in certain forms of neuronal plasticity. These observations led us to examine the role of the MAPK pathway in clock entrainment. Here we report that pharmacological disruption of light-induced MAPK pathway activation in the SCN uncouples photic input from clock entrainment, as assessed by locomotor activity phase. In the absence of photic stimulation, transient disruption of MAPK signaling in the SCN did not alter clock-timing properties. We also report that signaling via the Ca(2+)/calmodulin kinase pathway functions upstream of the MAPK pathway, coupling light to activation of the MAPK pathway. Together these results delineate key intracellular signaling events that underlie light-induced clock entrainment.

Animals↗
PubMed1991

Neurospora crassa clock-controlled genes are regulated at the level of transcription.

Although an extensive number of biological processes are under the daily control of the circadian biological clock, little is known about how the clock maintains its regulatory networks within a cell. An important aspect of this temporal control is the daily control of gene expression. Previously we identified two morning-specific genes that are regulated by the clock through daily control of gene expression (J. Loros, S. Denome, and J.C. Dunlap, Science 243:385-388, 1989). We have now introduced a method for transcriptional analysis in Neurospora crassa and used this nuclear run-on procedure to show that regulation of mRNA abundance for these two morning-specific genes occurs at the level of transcription. This transcriptional regulation by the circadian clock provides a basis for isolating circadian rhythm mutants.

Amanitins↗
PubMed2004

In search of the "hair cycle clock": a guided tour.

The hair follicle, a unique characteristic of mammals, represents a stem cell-rich, prototypic neuroectodermal-mesodermal interaction system. This factory for pigmented epithelial fibers is unique in that it is the only organ in the mammalian body which, for its entire lifetime, undergoes cyclic transformations from stages of rapid growth (anagen) to apoptosis-driven regression (catagen) and back to anagen, via an interspersed period of relative quiescence (telogen). While it is undisputed that the biological "clock" that drives hair follicle cycling resides in the hair follicle itself, the molecular nature of the underlying oscillator system remains to be clarified. To meet this challenge is of profound general interest, since numerous key problems of modern biology can be studied exemplarily in this versatile model system. It is also clinically important, since the vast majority of patients with hair growth disorders suffers from an undesired alteration of hair follicle cycling. Here, we sketch basic background information and key concepts that one needs to keep in mind when exploring the enigmatic "hair cycle clock"(HCC), and summarize competing models of the HCC. We invite the reader on a very subjective guided tour, which focuses on our own trials, errors, and findings toward the distant goal of unravelling one of the most fascinating mysteries of biology: Why does the hair follicle cycle at all? How does it do it? What are the key players in the underlying molecular controls? Attempting to offer at least some meaningful answers, we share our prejudices and perspectives, and define crucial open questions.

Animals↗
PubMed1993

New findings regarding light intensity and its effects as a zeitgeber in the Sprague-Dawley rat.

Circadian rhythmicities are oscillations of physiological cycles designed to create temporal organization. Circadian rhythms ensure that physiological mechanisms are expressed in proper relationship to each other and the 24 hour day. Light is the main zeitgeber ("time giver") for biological clocks. The daily variations in light intensity from dawn to dusk, and seasonally due to the rotation of the earth, act upon organisms to give them photoperiodic information. This entrainment allows them to vary biologically to prepare for reproduction, hibernation, migration and the daily adaptations necessary for survival. In most mammals, the suprachiasmatic nucleus of the anterior hypothalamus has been implicated as the central diving mechanism of circadian rhythmicity. The photic input from the retina, via the retino-hypothalamic tract, and modulation from the pineal gland help regulate the clock. In this study we investigated the effects of low light intensity on the circadian system of the Sprague-Dawley rat. A series of light intensity experiments were conducted to determine if a light level of 0.1 Lux will maintain entrained circadian rhythms of feeding, drinking, and locomotor activity.

Activity Cycles↗
PubMed1999

Chronopharmacology and its impact on antihypertensive treatment.

Circadian rhythms have been documented throughout the plant and animal kingdom at every level of eukariotic organization. Circadian rhythms are endogenous in nature, driven by oscillators or clocks, and persist under free-running (e.g. constant darkness) conditions. The genes expressing the biological clock have been identified in various species. The important feature of endogeneous biological rhythms is their anticipatory character. Rhythmicity inherent to all living systems, allows them to adapt more easily and to better survive under changing environmental conditions during the 24 hours of a day as well as during changing seasons. Having this in mind it is easy to conceive that not only must the right amount of the right substance be at the right place, but also this must occur at the right time. Also in man nearly all functions of the body including those influencing pharmacokinetic parameters such as drug absorption and distribution, drug metabolism and renal elimination display significant daily variations. Also the onset and symptoms of diseases such as coronary infarction, angina pectoris, stroke, ventricular tachycardia are circadian phase dependent. Myocardial infarction and angina attacks as well as silent ischemias (ST-segment depression) in stable angina pectoris have an early morning peak between 8-12 h. In contrast, ECG abnormalities and angina attacks in variant angina mainly occur at night. Blood pressure and heart rate in normotensives and essential (primary) hypertensive patients display highest values during daytime followed by a nightly drop and an early morning rise. In about 70% of forms of secondary hypertension (e.g. renal disease, hyperthyroidisms, hormonal diseases, gestational hypertension), however, this rhythmic pattern is abolished or even reversed exhibiting nightly peaks in blood pressure. This form of hypertension is accompanied by increased end organ damages. Thus, different subtypes of a disease (angina pectoris, hypertension) can display different circadian patterns in symptoms. These observations are a challenge for basic and clinical research to get a better understanding on the underlying mechanisms of regulation. Moreover, they call for a circadian time-specified drug treatment. From above it is evident that pharmacokinetics may also not be constant within a day. Chronopharmacokinetics have been shown for several cardiovascular active drugs (propranolol, nifedipine, verapamil, enalapril, isosorbide-5-mononitrate, digoxin, etc.). Far more drugs were shown to display significant daily variations in their effects (chronopharmacodynamics, chronotoxicology) even after chronic application or constant infusion. In conclusion, there is clear evidence that the dose/concentration-response relationship of drugs can be significantly dependent on the time of day. Thus, circadian time has to be taken into account as an important variable influencing a drug's pharmacokinetics and/or its effects or side effects.

Animals↗
PubMed1996

Circadian clocks in prokaryotes.

Prokaryotes have long been thought incapable of expressing circadian (daily) rhythms. Recently, however, such biological 'clocks' have been discovered in several species of cyanobacteria. These endogenous timekeepers control gene expression on a global level in cyanobacteria. Even in cyanobacterial cultures that are growing with average doubling times more rapid than one per 24 h, the circadian clock controls gene expression and cell division. We have isolated mutants of the cyanobacterial circadian pacemaker and are currently characterizing the loci responsible for their altered period phenotypes.

Cell Division↗
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↗
PubMed1996

Persistence of nonphotic phase shifts in hamsters after serotonin depletion in the suprachiasmatic nucleus.

Serotonin-containing fibres (5-HT) project from the raphe complex to the suprachiasmatic nucleus (SCN). Previous studies have suggested that this pathway may be involved in nonphotic resetting of the circadian clock. For example, 5-HT agonists are capable of phase shifting the biological clock both in vivo and in vitro, producing phase response curves (PRCs) similar in shape to those of other nonphotic stimuli. Therefore we studied the role of the serotonergic projection to the SCN in nonphotic phase shifts by bilateral injection of the selective 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT) onto the SCN of hamsters. About 50 days after the administration of the neurotoxin, the 5-HT and 5-HIAA (5-hydroxyindole acetic acid) levels were severely depleted in the SCN, as revealed by high performance liquid chromatography (HPLC), and immunocytochemistry (ICC). The average level of 5-HT depletion was 88% in Experiment 1 and 95% in Experiment 2. This treatment had no effect on the magnitude of phase shifts produced by 3 h of novelty-induced wheel-running starting at circadian time (CT) 4, the peak of the advance region of the PRC to this stimulus. The effect of 5-HT depletion on shifts produced by running at CT 22 were inconclusive because of changes in the behavior of control animals. No changes in the phase angle of entrainment of animals in a 14:10 light:dark (LD) cycle were detected in depleted animals. The results suggest that the 5-HT projection from the raphe to the SCN is not essential for activity-induced phase shifts in hamsters.

5,7-Dihydroxytryptamine↗
PubMed2006

Phosphorylation of SPICK2, an AKT2 channel homologue from Samanea motor cells.

SPICK2, a homologue of the weakly-inward-rectifying Shaker-like Arabidopsis K channel, AKT2, is a candidate K+-influx channel participating in light- and clock-regulated leaf movements of the legume, Samanea saman. Light and the biological clock regulate the in situ K+-influx channel activity differentially in extensor and flexor halves of the pulvinus (the S. saman leaf motor organ), and also-though differently-the transcript level of SPICK2 in the pulvinus. This disparity between the in situ channel activity versus its candidate transcript, along with the sequence analysis of SPICK2, suggest an in situ regulation of the activity of SPICK2, possibly by phosphorylation and/or by interaction with cAMP. Consistent with this (i) the activity of the voltage-dependent K+-selective fraction of the inward current in extensor and flexor cells was affected differentially in whole-cell patch-clamp assays promoting phosphorylation (using the protein phosphatase inhibitor okadaic acid); (ii) several proteins in isolated plasma membrane-enriched vesicles of the motor cells underwent phosphorylation without an added kinase in conditions similar to patch-clamp; and (iii) the SPICK2 protein was phosphorylated in vitro by the catalytic subunit of the broad-range cAMP-dependent protein kinase. All of these results are consistent with the notion that SPICK2 is the K+-influx channel, and is regulated in vivo directly by phosphorylation.

Animals↗
PubMedDate not supplied

Clock genes of Mammalian cells: practical implications in tissue culture.

The clock genes family is expressed by all the somatic cells driving central and peripheral circadian rhythms through transcription/translation feedback loops. The circadian clock provides a local time for a cell and a way to integrate the normal environmental changes to smoothly adapt the cellular machinery to new conditions. The central circadian rhythm is retained in primary cultures by neurons of the suprachiasmatic nuclei. The peripheral circadian rhythms of the other somatic cells are progressively dampened down up to loss unless neuronal signals of the central clock are provided for re-entrainment. Under typical culture conditions (obscurity, 37 +/- 1 degrees C, 5-7% CO(2)), freshly explanted peripheral cells harbor chaotic expression of clock genes for 12-14 h and loose, coordinated oscillating patterns of clock components. Cells of normal or cancerous phenotypes established in culture harbor low levels of clock genes idling up to the re-occurrence of new synchronizer signals. Synchronizers are physicochemical cues (like thermic oscillations, short-term exposure to high concentrations of serum or single medium exchange) able to re-induce molecular oscillations of clock genes. The environmental synchronizers are integrated by response elements located in the promoter region of period genes that drive the central oscillator complex (CLOCK:BMAL1 and NPAS2:BMAL1 heterodimers). Only a few cell lines from different species and lineages have been tested for the existence or the functioning of a circadian clockwork. The best characterized cell lines are the immortalized SCN2.2 neurons of rat suprachiasmatic nuclei for the central clock and the Rat-1 fibroblasts or the NIH/3T3 cells for peripheral clocks. Isolation methods of fragile cell phenotypes may benefit from research on the biological clocks to design improved tissue culture media and new bioassays to diagnose pernicious consequences for health of circadian rhythm alterations.

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

Instability of Hes7 protein is crucial for the somite segmentation clock.

During somitogenesis, a pair of somites buds off from the presomitic mesoderm every 2 hours in mouse embryos, suggesting that somite segmentation is controlled by a biological clock with a 2-hour cycle. Expression of the basic helix-loop-helix factor Hes7, an effector of Notch signaling, follows a 2-hour oscillatory cycle controlled by negative feedback; this is proposed to be the molecular basis for the somite segmentation clock. If the proposal is correct, this clock should depend crucially on the short lifetime of Hes7. To address the biological importance of Hes7 instability, we generated mice expressing mutant Hes7 with a longer half-life (approximately 30 min compared with approximately 22 min for wild-type Hes7) but normal repressor activity. In these mice, somite segmentation and oscillatory expression became severely disorganized after a few normal cycles of segmentation. We simulated this effect mathematically using a direct autorepression model. Thus, instability of Hes7 is essential for sustained oscillation and for its function as a segmentation clock.

Animals↗
PubMedDate not supplied

[The studies of temporal and spatial characteristics of somitogenesis in fish embryos].

New data were obtained corroborating that somitogenesis is a rhythmic process, in which the time of somite formation is strictly constant. This constant (tau s) can be considered as a natural unit of developmental "biological clock" characterizing rhythmic processes. The constant tau s can be determined with an exceptional accuracy that has no analogs among the known biological processes. This fact alone suggests that the accuracy of developmental clock is very high. In addition to the constancy of tau s, all forming somites have equal linear size along the notochord axis. In the process with strictly constant temporal and spatial factors, time plays the leading role in triggering the formation of new somite. This became clear in studies of twin embryos. Both embryos had the same number of somites but they were shorter than in the normal embryos. Also, we measured the length of head and both segmented and unsegmented caudal parts of the trunk. Combined with the published data on somitogenesis, our results suggest that the previously proposed scheme for the role of developmental clock in embryogenesis predicts: (1) a possible loss of some embryonic stages without serious consequences for subsequent development and (2) periodic switching on/off any embryonic processes (at the molecular, cellular, or supercellular level) with intervals multiple to tau s.

Animals↗
PubMed2004

Entrainment dissociates transcription and translation of a circadian clock gene in neurospora.

Circadian systems coordinate the daily sequence of events in cells, tissues, and organisms. In constant conditions, the biological clock oscillates with its endogenous period, whereas it is synchronized to the 24 hr light:dark cycle in nature. Here, we investigate light entrainment of Neurospora crassa to photoperiods that mimic seasonal changes. Clock gene (frequency, or frq) RNA levels directly reflect the light environment in all photoperiods, whereas the FRQ protein follows neither RNA levels nor light transitions. Induction of frq RNA and protein can be dissociated by as much as 6 hr, depending on photoperiod. The phase of entrainment at the physiological level (e.g., asexual spore development) correlates with FRQ protein. Thus, a dissociation of transcription, translation, and protein stability is fundamental to circadian entrainment of Neurospora. Our findings suggest that simple feedback models are insufficient to explain the molecular circadian mechanisms under entrained conditions and that clock control of light input pathways involves posttranscriptional regulation. The regulators mediating the dissociation between RNA and protein levels are still unknown and will be the key to understanding both circadian timing at the molecular level and how the clock exerts control over many cellular processes.

Acclimatization↗
PubMed2004

Transcriptional oscillation of canonical clock genes in mouse peripheral tissues.

BACKGROUND: The circadian rhythm of about 24 hours is a fundamental physiological function observed in almost all organisms from prokaryotes to humans. Identification of clock genes has allowed us to study the molecular bases for circadian behaviors and temporal physiological processes such as hormonal secretion, and has prompted the idea that molecular clocks reside not only in a central pacemaker, the suprachiasmatic nuclei (SCN) of hypothalamus in mammals, but also in peripheral tissues, even in immortalized cells. Furthermore, previous molecular dissection revealed that the mechanism of circadian oscillation at a molecular level is based on transcriptional regulation of clock and clock-controlled genes. RESULTS: We systematically analyzed the mRNA expression of clock and clock-controlled genes in mouse peripheral tissues. Eight genes (mBmal1, mNpas2, mRev-erbalpha, mDbp, mRev-erbbeta, mPer3, mPer1 and mPer2; given in the temporal order of the rhythm peak) showed robust circadian expressions of mRNAs in all tissues except testis, suggesting that these genes are core molecules of the molecular biological clock. The bioinformatics analysis revealed that these genes have one or a combination of 3 transcriptional elements (RORE, DBPE, and E-box), which are conserved among human, mouse, and rat genome sequences, and indicated that these 3 elements may be responsible for the biological timing of expression of canonical clock genes. CONCLUSIONS: The observation of oscillatory profiles of canonical clock genes is not only useful for physiological and pathological examination of the circadian clock in various organs but also important for systematic understanding of transcriptional regulation on a genome-wide basis. Our finding of the oscillatory expression of canonical clock genes with a temporal order provides us an interesting hypothesis, that cyclic timing of all clock and clock-controlled genes may be dependent on several transcriptional elements including 3 known elements, E-box, RORE, and DBPE.

ARNTL Transcription Factors↗