Loss of circadian rhythmicity in aging mPer1-/-mCry2-/- mutant mice (original) (raw)
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Disruption of mCry2 restores circadian rhythmicity in mPer2 mutant mice
Genes & Development, 2002
Many biochemical, physiological, and behavioral processes display daily rhythms generated by an internal timekeeping mechanism referred to as the circadian clock. The core oscillator driving this clock is located in the ventral part of the hypothalamus, the so calledsuprachiasmatic nuclei (SCN). At the molecular level, this oscillator is thought to be composed of interlocking autoregulatory feedback loops involving a set of clock genes. Among the components driving the mammalian circadian clock are the Period 1 and 2 (mPer1 and mPer2) and Cryptochrome 1 and 2 (mCry1 and mCry2) genes. A mutation in themPer2 gene leads to a gradual loss of circadian rhythmicity in mice kept in constant darkness (DD). Here we show that inactivation of the mCry2 gene in mPer2 mutant mice restores circadian rhythmicity and normal clock gene expression patterns. Thus,mCry2 can act as a nonallelic suppressor of mPer2, which points to direct or indirect interactions of PER2 and CRY2 proteins. In marked cont...
mCRY1 and mCRY2 Are Essential Components of the Negative Limb of the Circadian Clock Feedback Loop
Cell, 1999
to coordinated circadian outputs from the nucleus, ultimately regulating rhythms in physiology and behavior (Welsh et al., 1995; Liu et al., 1997; Herzog et al., 1998). Circadian clocks also appear to exist in several peripheral tissues of mammals that are synchronized by the SCN (Balsalobre et al., 1998; Sakamoto et al., 1998; Zylka et al., 1998a). Pediatric Service Massachusetts General Hospital and A number of mammalian genes have been cloned recently that resemble the well-studied circadian clock Harvard Medical School Boston, Massachusetts 02114 genes from the fruit fly Drosophila melanogaster (reviewed in Dunlap, 1999
Targeted Disruption of the mPer3 Gene: Subtle Effects on Circadian Clock Function
Molecular and Cellular Biology, 2000
Neurons in the mammalian suprachiasmatic nucleus (SCN) contain a cell-autonomous circadian clock that is based on a transcriptional-translational feedback loop. The basic helix-loop-helix–PAS proteins CLOCK and BMAL1 are positive regulators and drive the expression of the negative regulators CRY1 and CRY2, as well as PER1, PER2, and PER3. To assess the role of mouse PER3 (mPER3) in the circadian timing system, we generated mice with a targeted disruption of the mPer3 gene. Western blot analysis confirmed the absence of mPER3-immunoreactive proteins in mice homozygous for the targeted allele. mPer1 , mPer2 , mCry1 , and Bmal1 RNA rhythms in the SCN did not differ between mPER3-deficient and wild-type mice. Rhythmic expression of mPer1 and mPer2 RNAs in skeletal muscle also did not differ between mPER3-deficient and wild-type mice. mPer3 transcripts were rhythmically expressed in the SCN and skeletal muscle of mice homozygous for the targeted allele, but the level of expression of the...
Neuron, 1998
until recently, it has remained unclear whether the circadian pacemakers of these various organisms share a common molecular mechanism (Dunlap, 1998). Perhaps the circadian system that has been best characterized at the molecular genetic level is that of Drosophila melanogaster (Rosato et al., 1997a; Young, Michael W. Young, § Charles J. Weitz, ‡ 1998). Two oscillator components, period (per) and and Joseph S. Takahashi* † timeless tim), express rhythms in messenger RNA and * Department of Neurobiology and Physiology and protein abundance (Hardin et al., 1990; Edery et al., National Science Foundation Center for 1994; Sehgal et al., 1995; Myers et al., 1996). Mutations Biological Timing in these genes affect both overt circadian rhythms of † Howard Hughes Medical Institute eclosion and locomotor activity (Konopka and Benzer, Northwestern University 1971; Sehgal et al., 1994) as well as molecular oscilla-Evanston, Illinois 60208 tions of per and tim gene products (Hardin et al., 1990; ‡ Department of Neurobiology Sehgal et al., 1995). The per and tim genes are involved in Harvard Medical School a negative autoregulatory feedback loop that underlies Boston, Massachusetts 02115 overt rhythm generation (Hardin et al., 1990; Zeng et al., § Laboratory of Genetics and 1994; Sehgal et al., 1995). The TIMELESS (dTIM) and National Science Foundation Center PERIOD (dPER) proteins physically interact and regulate for Biological Timing the expression of their own mRNAs following nuclear The Rockefeller University entry (Gekakis et al., 1995; Saez and Young, 1996). New York, New York 10021 Work over the past year has demonstrated a striking parallel between the mammalian and Drosophila circadian systems. The Clock gene regulates the period and Summary persistence of circadian rhythms in mice (Vitaterna et al., 1994). The molecular identification of Clock first hinted at We report the cloning and mapping of mouse (mTim) the conservation of the circadian system between flies and human (hTIM) orthologs of the Drosophila timeless and mammals as it encodes a novel basic helix-loop-(dtim) gene. The mammalian Tim genes are widely exhelix (bHLH) PAS (PER-ARNT-SIM) transcription factor pressed in a variety of tissues; however, unlike Dro-(Antoch et al., 1997; King et al., 1997). Subsequently, sophila, mTim mRNA levels do not oscillate in the suthree mammalian Per homologs, mPer1, mPer2, and prachiasmatic nucleus (SCN) or retina. Importantly, mPer3, have been identified. All three genes show oscil-hTIM interacts with the Drosophila PERIOD (dPER) lations in mRNA abundance in the SCN and retina (Alprotein as well as the mouse PER1 and PER2 proteins brecht et al., 1997; Shearman et al., 1997; Shigeyoshi in vitro. In Drosophila (S2) cells, hTIM and dPER interet al., 1997; Sun et al., 1997; Tei et al., 1997; Takumi et act and translocate into the nucleus. Finally, hTIM and al., 1998a, 1998b; Zylka et al., 1998). Recent work has mPER1 specifically inhibit CLOCK-BMAL1-induced shown that CLOCK heterodimerizes with a bHLH-PAS transactivation of the mPer1 promoter. Taken topartner known as BMAL1 or MOP3 (Gekakis et al., 1998; gether, these results demonstrate that mTim and hTIM Hogenesch et al., 1998). The CLOCK-BMAL1 complex are mammalian orthologs of timeless and provide a transactivates the mPer1 promoter specifically via E box framework for a basic circadian autoregulatory loop elements contained within the first 1.2 kb upstream of in mammals. the gene (Gekakis et al., 1998). Concomitantly, the corresponding genes in Drosophila were discovered with the
PLOS Computational Biology, 2021
Modification of the Per2 clock gene in mPer2Luc reporter mice significantly alters circadian function. Behavioral period in constant dark is lengthened, and dissociates into two distinct components in constant light. Rhythms exhibit increased bimodality, enhanced phase resetting to light pulses, and altered entrainment to scheduled feeding. Mechanistic mathematical modelling predicts that enhanced protein interactions with the modified mPER2 C-terminus, combined with differential clock regulation among SCN subregions, can account for effects on circadian behavior via increased Per2 transcript and protein stability. PER2::LUC produces greater suppression of CLOCK:BMAL1 E-box activity than PER2. mPer2Luc carries a 72 bp deletion in exon 23 of Per2, and retains a neomycin resistance cassette that affects rhythm amplitude but not period. The results show that mPer2Luc acts as a circadian clock mutation illustrating a need for detailed assessment of potential impacts of c-terminal tags i...
Biochemical and Biophysical Research Communications, 1998
lecular mechanisms involved in the circadian clock are A superfamily gene which encodes a bHLH (basic just beginning to be understood in mammals, substanhelix-loop-helix)/PAS transcription factor, BMAL1, tial progress has been made during the past year by was cloned and sequenced from rat cDNA. A robust the cloning of a mouse clock gene Clock (6, 7). Clock was circadian rhythm of rat BMAL1 expression was deshown to encode a transcription factor which contains a tected by in situ hybridization in the suprachiasmatic protein-protein interaction sequence known as a PAS nucleus (SCN), the site of the circadian clock, with the domain and a DNA binding sequence, basic helix-loophighest level at the subjective night. Less prominent helix (bHLH) (7). However, the expression of Clock in and completely reversed circadian rhythms of rBMAL1 the SCN did not oscillate (8, 9). In the same year, sev-mRNA were observed in the piriform and parietal coreral members of a PAS family were cloned from mamtices. The hybridization signals of rBMAL1 mRNA were malian DNA, which includes homologues of human also detected in the olfactory bulb, hippocampus, and Arnt (BMAL1 or MOP3) (10, 11) and of the Drosophila cerebellum. Since the product of rBMAL1 was recently clock gene Per (mPer1 and mPer2) (8, 9). Although the demonstrated to dimerize with the protein of a mammalian clock gene, Clock, and the protein complex was functions of these genes are not yet clarified, mRNA shown to bind the E Box in the promoter region of levels of mPer1 and mPer2 showed circadian oscillation mPer1 (a mouse homologue to Drosophila clock gene, in the mouse SCN (8, 9). In addition, the gene tran-Per), rBMAL1 possibly plays a critical role in the clock script was increased in response to a short light pulse mechanism generating the circadian oscillation in (12-14). Because of structural similarities to Drosophrats. ᭧ 1998 Academic Press EMBL, and GenBank nucleotide sequence databases under Accesbe the mutants of BMAL1 homologue and Drosophila sion No. AB012600.
European Journal of Neuroscience, 2000
The circadian clock in the hypothalamic suprachiasmatic nuclei (SCN) regulates the pattern of melatonin secretion from the pineal gland such that the duration of release re¯ects the length of the night. This seasonally speci®c endocrine cue mediates annual timing in photoperiodic mammals. The aim of this study was to investigate how changes in photoperiod in¯uence the cyclic expression of recently identi®ed clock gene products (mPER and mTIM) in the SCN of a highly seasonal mammal, the Siberian hamster (Phodopus sungorus). Immunocytochemical studies indicate that the abundance of both mPER1 and mPER2 (but not mTIM) in the SCN exhibits very pronounced, synchronous daily cycles, peaking approximately 12 h after lights-on. These rhythms are circadian in nature as they continue approximately under free-running conditions. Their circadian waveform is modulated by photoperiod such that the phase of peak mPER expression is prolonged under long photoperiods. mPER1 protein is also expressed in the pars tuberalis of Siberian hamsters. In hamsters adapted to long days, the expression of mPER1 is elevated at the start of the light phase. In contrast, there is no clear elevation in mPER1 levels in the pars tuberalis of hamsters held on short photoperiods. These results indicate that core elements of the circadian clockwork are sensitive to seasonal time, and that encoding and decoding of seasonal information may be mediated by the actions of these transcriptional modulators.
Molecular components of the mammalian circadian clock
Human Molecular Genetics, 2006
Circadian rhythms are 24-h oscillations in behavior and physiology, which are internally generated and function to anticipate the environmental changes associated with the solar day. A conserved transcriptional -translational autoregulatory loop generates molecular oscillations of 'clock genes' at the cellular level. In mammals, the circadian system is organized in a hierarchical manner, in which a master pacemaker in the suprachiasmatic nucleus (SCN) regulates downstream oscillators in peripheral tissues. Recent findings have revealed that the clock is cell-autonomous and self-sustained not only in a central pacemaker, the SCN, but also in peripheral tissues and in dissociated cultured cells. It is becoming evident that specific contribution of each clock component and interactions among the components vary in a tissue-specific manner. Here, we review the general mechanisms of the circadian clockwork, describe recent findings that elucidate tissue-specific expression patterns of the clock genes and address the importance of circadian regulation in peripheral tissues for an organism's overall well-being.