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At least 757 records · Page 42Linked to original sources
PubMed2003

Expression of mCLOCK and other circadian clock-relevant proteins in the mouse suprachiasmatic nuclei.

Circadian timing in mammals is based upon the cell-autonomous clockwork located in the suprachiasmatic nuclei (SCN) of the hypothalamus. It is thought to involve interlocked feedback loops in which periodic transcriptional drive to core clock genes is mediated by CLOCK/BMAL1 heterodimers. Negative-feedback actions of the encoded proteins PER and CRY terminate this phase of the cycle. In lower species, rhythmic abundance of the mCLOCK homologue initiates the subsequent cycle. By contrast, it is proposed that the new circadian cycle in mammals is triggered by indirect, positive transcriptional actions leading to a subsequent surge in BMAL1. The aim of this study was to test predictions made by this model concerning the behaviour of the native clock factor mCLOCK in the mouse SCN. Using in situ hybridization, immunocytochemistry, Western blotting and immunoprecipitation, we demonstrate constitutive expression of mCLOCK as a nuclear antigen in the SCN. mCLOCK forms alternating, periodic associations with either mBMAL1 or the negative regulators mPER and mCRY. The results confirm predictions made by the "two-loop" model of the mouse clock, and further highlight the role of interlocked cycles of positive and negative transcriptional regulatory complexes at the heart of the circadian clockwork.

ARNTL Transcription Factors↗
PubMed2003

Clock genes and the long-term regulation of prolactin secretion: evidence for a photoperiod/circannual timer in the pars tuberalis.

Prolactin secretion is regulated by photoperiod through changes in the 24-h melatonin profile and displays circannual rhythmicity under constant photoperiod. These two processes appear to occur principally within the pituitary gland, controlled by the pars tuberalis. This is evident because: (i) hypothalamic-pituitary disconnected (HPD) sheep show marked changes in prolactin secretion in response to switches in photoperiod and manipulations of melatonin, similar to brain-intact controls; (ii) HPD sheep also show photoperiod-specific, long-term cycles in prolactin secretion under constant long or short days, with the timing maintained even when prolactin secretion is blocked for 2-3 months; and (iii) pars tuberalis cells, but not lactotrophs, express high concentrations of melatonin (MT1) receptor, and exhibit a duration-sensitive, cAMP-dependant, inhibitory response to physiological concentrations of melatonin. This suggests the existence of an intrinsic, reversible photoperiod-circannual timer in pars tuberalis cells. A full complement of clock genes (Bmal1, Clock, Per1, Per2, Cry1 and Cry2) are expressed in the ovine pars tuberalis, and undergo 24-h cyclical expression as observed in a cell autonomous, circadian clock. Activation of Per genes occurs in the early day (melatonin off-set), while activation of Cry genes occurs in the early night (melatonin on-set). This temporal association is evident under both long and short days, thus the Per-Cry interval varies directly with photoperiod. Because, PER : CRY, protein : protein interactions affect stability, nuclear entry and gene transcription based on rodent data, the change in phasing of Per/Cry expression provides a potential mechanism for decoding the long day/short day melatonin signal. A speculative, but testable, extension of this hypothesis is that intrinsically regulated changes in the phase of Per/Cry rhythms, regulates both photorefractoriness and the generation of circannual rhythms in prolactin secretion.

Animals↗
PubMed2003

The circadian clock: a manager of biochemical processes within the organism.

The periodic succession of night and day has influenced life on earth for millions of years. Many organisms have "internalized" this periodic change in the form of the circadian clock. Its main function is to organize the time course of biochemical, physiological and behavioural processes thereby optimizing an organism's performance in anticipating changing environmental conditions. Therefore, it is important to understand the underlying mechanisms that connect the core pacemaker, which is located in the suprachiasmatic nuclei (SCN) of the hypothalamus, with peripheral organs. Several laboratories set out to identify genes that are under the influence of the circadian clock. It appears that the circadian clock coordinates transcription of key metabolic pathways thereby orchestrating the time course of physiological and behavioural processes. We review these investigations and put our experiments, the comparison of gene expression in SCN tissue of Per2 mutant and wild-type mice, in the context of these findings.

Animals↗
PubMed2006

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

In most mammals, daily rhythms in physiology are driven by a circadian timing system composed of a master pacemaker in the suprachiasmatic nucleus (SCN) and peripheral oscillators in most body cells. The SCN clock, which is phase-entrained by light-dark cycles, is thought to synchronize subsidiary oscillators in peripheral tissues, mainly by driving cyclic feeding behavior. Here, we examined the expression of circadian clock genes in the SCN and the liver of the common vole Microtus arvalis, a rodent with ultradian activity and feeding rhythms. In these animals, clock-gene mRNAs accumulate with high circadian amplitudes in the SCN but are present at nearly constant levels in the liver. Interestingly, high-amplitude circadian liver gene expression can be elicited by subjecting voles to a circadian feeding regimen. Moreover, voles with access to a running wheel display a composite pattern of circadian and ultradian behavior, which correlates with low-amplitude circadian gene expression in the liver. Our data indicate that, in M. arvalis, the amplitude of circadian liver gene expression depends on the contribution of circadian and ultradian components in activity and feeding rhythms.

Animal Feed↗
PubMed2003

Circadian rhythms. Liver regeneration clocks on.

In some simple protozoans and unicellular algae, the cell cycle clock is strongly influenced by the circadian clock, such that mitotic cell division takes place only at certain times of the day. Now, as Schibler reports in his Perspective, new work on regenerating liver cells in mice (Matsuo et al.) reveals that the cell cycle clock of mammalian cells is also under the yoke of the master circadian oscillator.

ARNTL Transcription Factors↗
PubMed2006

Circadian intraocular pressure rhythm is generated by clock genes.

PURPOSE: The present study in a mouse model was undertaken to reveal the role of the circadian clock genes Cry1 and Cry2 in generation of 24-hour intraocular pressure (IOP) rhythm. METHODS: IOP was measured at eight time points daily (circadian time [CT] 0, 3, 6, 9, 12, 15, 18, and 21 hours), using a microneedle method in four groups of C57BL/6J mice (groups 1 and 3, wild-type; groups 2 and 4, Cry-deficient [Cry1-/-Cry2-/-]). During the IOP measurements, mice in groups 1 and 2 were maintained in a 12-hour light-dark cycle (LD), whereas mice in groups 3 and 4 were kept in a constant darkness (DD) that started 24 to 48 hours before the measurements. Circadian IOP variations in each group were evaluated by one-way analysis of variance (ANOVA) and Scheffé tests. RESULTS: In wild-type mice living in LD conditions, pressures measured in the light phase were significantly lower than those in the dark phase. This daily rhythm was maintained under DD conditions with low pressure in the subjective day and high pressure in the subjective night. In contrast, Cry-deficient mice did not show significant circadian changes in IOP, regardless of environmental light conditions. CONCLUSIONS: These findings demonstrate that clock oscillatory mechanisms requiring the activity of core clock genes are essential for the generation of a circadian rhythm of intraocular pressure.

Animals↗
PubMed2004

Clock gene evolution and functional divergence.

In considering the impact of the earth's changing geophysical conditions during the history of life, it is surprising to learn that the earth's rotational period may have been as short as 4 h, as recently as 1900 million years ago (or 1.9 billion years ago). The implications of such figures for the origin and evolution of clocks are considerable, and the authors speculate on how this short rotational period might have influenced the development of the "protoclock" in early microorganisms, such as the Cyanobacteria, during the geological periodsin which they arose and flourished. They then discuss the subsequent duplication of clock genes that took place around and after the Cambrian period, 543 million years ago, and its consequences. They compare the relative divergences of the canonical clock genes, which reveal the Per family to be the most rapidly evolving. In addition, the authors use a statistical test to predict which residues within the PER and CRY families may have undergone functional specialization.

ARNTL Transcription Factors↗
PubMed2004

[Advances in studies of biological clock gene].

The circadian clock genes, which generate and control the running of the circadian rhythms, exist in organisms ranging from prokaryotes to mammals. The oscillator genes and its coding proteins compose the feedback loops of circadian system. The kind, number and regulating route of clock genes are characterized by living things at different evolution levels. The molecular mechanism of the run of circadian clock genes in cyanobacteria, neurospore, fruit fly, mouse and human being is introduced in this article.

Animals↗
PubMed2000

Disruption of synaptic transmission or clock-gene-product oscillations in circadian pacemaker cells of Drosophila cause abnormal behavioral rhythms.

To study the function of clock-gene-expressing neurons, the tetanus-toxin light chain (TeTxLC), which blocks chemical synaptic transmission, was expressed under the control of promoters of the clock genes period (per) and timeless (tim), each fused to GAL4-encoding sequences. Although TeTxLC did not affect cycling of a clock-gene product at the gross level, it disrupted the rhythmic behavior of adult Drosophila. In constant darkness, the proportion of rhythmic flies was reduced in flies expressing active TeTxLC compared to controls, including those expressing inactive toxin. The behavior of TeTxLC-expressing flies was less synchronized to light:dark cycles than that of controls. To determine which neurons are responsible for these effects on behavior, the toxin was also expressed in restricted subsets of per/tim-expressing, laterally located pacemaker neurons by expressing TeTxLC under the control of a driver in which GAL4-encoding sequences are fused to the promoter of the pigment dispersing factor (pdf) gene. pdf-gal4-driven TeTxLC expression had relatively little effect on behavioral rhythms, implying that per/tim neurons other than pdf-expressing lateral neurons participate in the generation of rhythmic behavior. In another set of experiments, period gene products were expressed under the control of per-gal4 or tim-gal4. This resulted in an increased level of PER protein in many brain cells and reduction of bioluminescence cycling reported by a per-luciferase transgene, especially in the case of per expression affected by tim-gal4. This indicates a disruption of the transcriptional feedback loop that is a part of the oscillatory mechanism underlying Drosophila's circadian rhythms. Consistent with this molecular defect, the proportion of rhythmic individuals in constant darkness was subnormal in flies expressing PER under the control of tim-gal4, and their behavior in light:dark cycles was abnormal.

Animals↗
PubMed2000

Circadian clocks in the mammalian brain.

Daily cycles in physiology and behaviour are probably a universal feature of multicellular organisms. These rhythms are predominantly driven by endogenous clocks with a periodicity approximating to one day, i.e. circadian. In mammals, the circadian clock governing activity/ rest, neuroendocrine and autonomic rhythms lies in the hypothalamus, in the suprachiasmatic nuclei (SCN). Intrinsic circadian oscillators are also present in the retina. The SCN "clockwork" is based on a cell autonomous, genetically determined mechanism. Mammalian homologues of a number of Drosophila genes which encode elements of the fly circadian mechanism have recently been identified. In Drosophila, the protein products of these genes interact in a negative feedback loop, establishing a circadian cycle in gene expression. Characterisation of the roles played by putative mammalian clock genes in the SCN, and how the emergent cellular signal imposes order over the entire neuraxis, will provide a fundamental contribution to our understanding of the molecular basis of behaviour. BioEssays 22:23-31, 2000.

Animals↗
PubMed2000

A clock-work somite.

Somites are transient structures which represent the most overt segmental feature of the vertebrate embryo. The strict temporal regulation of somitogenesis is of critical developmental importance since many segmental structures adopt a periodicity based on that of the somites. Until recently, the mechanisms underlying the periodicity of somitogenesis were largely unknown. Based on the oscillations of c-hairy1 and lunatic fringe RNA, we now have evidence for an intrinsic segmentation clock in presomitic cells. Translation of this temporal periodicity into a spatial periodicity, through somite formation, requires Notch signaling. While the Hox genes are certainly involved, it remains unknown how the metameric vertebrate axis becomes regionalized along the antero-posterior (AP) dimension into the occipital, cervical, thoracic, lumbar, and sacral domains. We discuss the implications of cell division as a clock mechanism underlying the regionalization of somites and their derivatives along the AP axis. Possible links between the segmentation clock and axial regionalization are also discussed. BioEssays 22:72-83, 2000.

Animals↗
PubMed2003

Expression of clock gene products in the suprachiasmatic nucleus in relation to circadian behaviour.

Circadian timing within the suprachiasmatic nucleus (SCN) is modelled around cell-autonomous, autoregulatory transcriptional/post-translational feedback loops, in which protein products of canonical clock genes Period and Cryptochrome periodically oppose transcription driven by CLOCK:BMAL complexes. Consistent with this model, mCLOCK is a nuclear antigen constitutively expressed in mouse SCN, whereas nuclear mPER and mCRY are expressed rhythmically. Peaking in late subjective day, mPER and mCRY form heteromeric complexes with mCLOCK, completing the negative feedback loop as levels of mPer and mCry mRNA decline. Circadian resetting by light or non-photic resetting (mediated by neuropeptide Y) involves acute up- and down-regulation of mPer mRNA, respectively. Expression of Per mRNA also peaks in subjective day in the SCN of the ground squirrel, indicating common clock and entrainment mechanisms for nocturnal and diurnal species. Oscillation within the SCN is dependent on intercellular signals, in so far as genetic ablation of the VPAC2 receptor for vasoactive intestinal polypeptide (VIP) suspends SCN circadian gene expression. The pervasive effect of the SCN on peripheral physiology is underscored by cDNA microarray analysis of the circadian gene expression in liver, which involves ca. 10% of the genome and almost all aspects of cell function. Moreover, the same molecular regulatory mechanisms driving the SCN appear also to underpin peripheral cycles.

Animals↗
PubMed2003

Influence of CLOCK gene polymorphism on circadian mood fluctuation and illness recurrence in bipolar depression.

Recent studies showed that a polymorphism (T to C nucleotide substitution) in the 3' flanking region of the human CLOCK gene is associated with diurnal preferences of human healthy subjects, with higher "eveningness" in subjects carrying at least one copy of the C allele. We investigated the possible role of CLOCK gene polymorphism in the regulation of diurnal mood fluctuations during a major depressive episode. Sample (n = 101) was collected, in the context of previously reported trials, among patients affected by bipolar disorder type I, depressive episode without psychotic features, free of psychotropic medications. Perceived mood levels were assessed three times a day with self-administered visual analogue scales. Genotype groups showed no significant difference in diurnal mood fluctuations. When stratifying the sample by including only patients with an adequate period of observation (duration of illness higher than 5 years, n = 69), we post-hoc observed a significantly higher recurrence rate in homozygotes for the C variant, which was almost double than that of the other genotype groups. This preliminary observation leads to hypothesize a role for the CLOCK gene polymorphism in the regulation of long-term illness recurrence in bipolar disorder. Given the post-hoc nature of the finding, replication in independent samples is necessary to confirm it.

Bipolar Disorder↗
PubMed2003

Genetic dissection of psychopathological symptoms: insomnia in mood disorders and CLOCK gene polymorphism.

We investigated the possible effect of the 3111T/C CLOCK gene polymorphism on sleep disorders in a sample of 620 patients affected by major depressive disorder (MDD) and bipolar disorder (BP). We detected a significantly higher recurrence of initial (P = 0.0001), middle (P = 0.0009), and early (P = 0.0008) insomnia in homozygotes for the C variant and a similar trend concerning decreased need of sleep in BP (P = 0.0074). Other demographic and clinical features were found not related with CLOCK polymorphisms. This preliminary observation leads to hypothesize a possible involvement of the CLOCK gene polymorphism in the sleep disregulations in MDD and BP.

Adult↗
PubMed2005

Insomnia improvement during antidepressant treatment and CLOCK gene polymorphism.

Sleep disturbances are commonly observed in mood disorders, and sleep manipulations can influence the clinical status. In the present study, we investigated the possible effect of the 3111 T/C circadian locomotor output cycles kaput (CLOCK) gene polymorphism on insomnia symptomatology during antidepressant treatment. One hundred seventy-eight inpatients were treated with fluvoxamine 300 mg/day (n = 147) or paroxetine 20-40 mg/day (n = 31), and either placebo or pindolol in a double blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression (HAM-D). We observed a significantly higher presence of insomnia throughout the trial in homozygotes for the C variant (P = 0.026). Other demographic and clinical features were found not to be related with CLOCK polymorphisms. Overall, our findings may suggest that CLOCK genotype influences the time course of insomnia during antidepressant treatment. This, together with previous findings on this polymorphism could lead to a further dissection of the complexity of mood disorders.

Adult↗
PubMed1994

Intergeneric complementation of a circadian rhythmicity defect: phylogenetic conservation of structure and function of the clock gene frequency.

The Neurospora crassa frequency locus encodes a 989 amino acid protein that is a central component, a state variable, of the circadian biological clock. We have determined the sequence of all or part of this protein and surrounding regulatory regions from additional fungi representing three genera and report that there is distinct, preferential conservation of the frequency open reading frame (ORF) as compared with non-coding sequences. Within the coding region, many of the domain hallmarks of the N. crassa protein are highly conserved, especially an internal region bearing the causative mutations in frq1 and frq7, the most extreme alleles in the frequency allelic series. Despite considerable diversity among the strains analyzed in terms of morphology, growth, circadian clock output and frq sequence, the ORF from the most distantly related fungus included in this study (Sordaria fimicola) rescues rhythmicity in a N.crassa frequency null strain. Both sequence conservation, and the ability of frequency from a genus displaying one developmental program to complement circadian defects in a separate genus with a distinct, clock-regulated developmental program, are consistent with a central role of the frequency gene product in a general circadian oscillator capable of controlling diverse outputs in a variety of systems.

Amino Acid Sequence↗
PubMed2000

Expression of mPer1 and mPer2, two mammalian clock genes, in murine bone marrow.

Although circadian variations in hematopoiesis have been well documented, the molecular mechanism of the circadian rhythms remains elusive. To determine if a clock system exists in bone marrow to mediate the circadian rhythms, we analyzed the expression of mPer1 and mPer2, both mouse homologues of the Drosophila period gene and known regulators of the clock system, in murine bone marrow by relative quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). We demonstrated that both genes were expressed in bone marrow. Furthermore, the expression patterns of mPer1 and mPer2 in total bone marrow cells exhibited two peaks over a 24-h period. In contrast, the expression patterns of these two genes in the Gr-1-positive cells isolated from bone marrow mainly contributed to one of the two peaks. These results indicate that a clock system exists in bone marrow and suggest that the circadian rhythms in bone marrow are lineage- and/or differentiation stage-dependent.

Analysis of Variance↗
PubMed1994

A mapped clock oscillator model for transmembrane electrical rhythmic activity in excitable cells.

Excitable cells such as smooth muscle, nerve, cardiac, and pancreatic beta cells exhibit rhythmic transmembrane depolarizations which have been modelled by nonlinear oscillators. This study deals with a general nonlinear oscillator with three different input portals. The oscillator consists of two coupled components: a clock which generates two interacting variables, and a transformer which maps the clock variables onto an observable output variable representing the transmembrane depolarizations. The clock determines the frequency, and the transformer determines the waveshape of the output. A computer model of the electrical rhythmic activity in gastric tissue was used as an example to illustrate the properties of the proposed oscillator model. A functional gastric oscillator may consist of a group of smooth muscles, or a group of interstitial cells of Cajal coupled to smooth muscles. Long, short and periodic pulses were applied to each input portal to examine their effects on the oscillator output with regards to amplitude and frequency characteristics, refractory properties, and entrainment properties, respectively.

Animals↗