Constitutive expression of the<i>Period1</i>gene impairs behavioral and molecular circadian rhythms

Numano, Rika; Yamazaki, Shin; Umeda, Nanae; Samura, Tomonori; Sujino, Mitsugu; Takahashi, Ri Ichi; Ueda, Masatsugu; Mori, Akiko; Yamada, Kinya; Sakaki, Yoshiyuki; Inouye, Shin Ichi T; Menaker, Michael; Tei, Hajime

doi:10.1073/pnas.0600060103

Cited by 60 publications

(49 citation statements)

References 41 publications

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“…Moreover, flies that express per and tim constitutively show defects in their response to pulses of light (Yang and Sehgal 2001). Overexpression of mPer1 also impairs normal entrainment and molecular oscillations in mammals (Numano et al 2006), supporting the idea that these responses depend upon cycling RNA. In further support of a role for transcription, new transcription factors continue to be identified as part of the clock mechanism.…”

Section: Rhythmic Clk-cyc Activity May Be Essential For a Functional mentioning

confidence: 73%

Probing the Relative Importance of Molecular Oscillations in the Circadian Clock

Zheng

Sehgal

2008

Genetics

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Circadian (24 hr) rhythms of behavior and physiology are driven by molecular clocks that are endogenous to most organisms. The mechanisms underlying these clocks are remarkably conserved across evolution and typically consist of auto-regulatory loops in which specific proteins (clock proteins) rhythmically repress expression of their own genes. Such regulation maintains 24-hr cycles of RNA and protein expression. Despite the conservation of these mechanisms, however, questions are now being raised about the relevance of different molecular oscillations. Indeed, several studies have demonstrated that oscillations of some critical clock genes can be eliminated without loss of basic clock function. Here, we describe the multiple levels at which clock gene/protein expression and function can be rhythmically regulated-transcription, protein expression, post-translational modification, and localization-and speculate as to which aspect of this regulation is most critical. While the review is focused on Drosophila, we include some discussion of mammalian clocks to indicate the extent to which the questions concerning clock mechanisms are similar, regardless of the organism under study. T HE light:dark cycle generated by the earth's rotation is the driving force of daily behavioral and physiological rhythms exhibited by most organisms. However, these daily (24 hr) rhythms are not just a passive response to the light:dark cycle; instead, an intrinsic timekeeping mechanism synchronizes physiological processes to the cyclic environment. The endogenous timekeeper is a self-sustained oscillator, termed the circadian clock, which can be entrained to environmental cues such as light and temperature (such environmental time signals are called zeitgebers), but more importantly, it free runs in constant conditions that lack environmental cues. In the past 20 years, genetic analysis of circadian rhythms in model organisms such as Drosophila, Neurospora, Arabidopsis, cyanobacteria, and mice has yielded considerable insight into the molecular mechanisms of circadian oscillators. Despite these advances, the question of how exactly a rhythm is generated is getting some attention again because a number of recent studies have challenged the simple models proposed initially. This review traces these developments in the field and then proposes a revised model that incorporates the old and new findings. While the focus is on the molecular mechanisms of the Drosophila melanogaster circadian clock, advances in other circadian systems will also be discussed to illustrate conserved mechanisms. Readers interested in circadian clock mechanisms of other organisms are encouraged to read recent reviews (Hastings and

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Section: Rhythmic Clk-cyc Activity May Be Essential For a Functional mentioning

confidence: 73%

Probing the Relative Importance of Molecular Oscillations in the Circadian Clock

Zheng

Sehgal

2008

Genetics

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“…Conversely, activation of D1 or D2 receptors increases Per1 transcription in striatum and retina (Imbesi et al, 2009;Yujnovsky et al, 2006). Notably, Per1 overexpression leads to longer circadian periods (Numano et al, 2006). Thus, elevated DA levels in DAT-KD À/À mice may lengthen circadian period by enhancing Per1 expression.…”

Section: Discussionmentioning

confidence: 99%

The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

et al. 2016

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a b s t r a c tEndogenous circadian (~24 h) clocks regulate key physiological and cognitive processes via rhythmic expression of clock genes. The main circadian pacemaker is the hypothalamic suprachiasmatic nucleus (SCN). Mood disorders, including bipolar disorder (BD), are commonly associated with disturbed circadian rhythms. Dopamine (DA) contributes to mania in BD and has direct impact on clock gene expression. Therefore, we hypothesized that high levels of DA during episodes of mania contribute to disturbed circadian rhythms in BD. The mood stabilizer valproic acid (VPA) also affects circadian rhythms. Thus, we further hypothesized that VPA normalizes circadian disturbances caused by elevated levels of DA. To test these hypotheses, we examined locomotor rhythms and circadian gene cycling in mice with reduced expression of the dopamine transporter (DAT-KD mice), which results in elevated DA levels and manialike behavior. We found that elevated DA signaling lengthened the circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants. In contrast, we found that VPA shortened circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants, hippocampal cell lines, and human fibroblasts from BD patients. Thus, DA and VPA have opposing effects on circadian period. To test whether the impact of VPA on circadian rhythms contributes to its behavioral effects, we fed VPA to DAT-deficient Drosophila with and without functioning circadian clocks. Consistent with our hypothesis, we found that VPA had potent activity-suppressing effects in hyperactive DAT-deficient flies with intact circadian clocks. However, these effects were attenuated in DAT-deficient flies in which circadian clocks were disrupted, suggesting that VPA functions partly through the circadian clock to suppress activity. Here, we provide in vivo and in vitro evidence across species that elevated DA signaling lengthens the circadian period, an effect remediated by VPA treatment. Hence, VPA may exert beneficial effects on mood by normalizing lengthened circadian rhythm period in subjects with elevated DA resulting from reduced DAT.

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“…PER proteins have the most dynamic rhythmicity and appear to be rate-limiting for the formation and nuclear accumulation of repressor protein complexes (21). Overexpression of Per1 increases period length (25). Mutations of CK1ε in hamsters and mice and of CK1␦ in humans alter PER dynamics and affect the circadian period (23,24,38).…”

Section: Discussionmentioning

confidence: 99%

Casein Kinase 1 Delta Regulates the Pace of the Mammalian Circadian Clock

Etchegaray

Machida

Noton

et al. 2009

Molecular and Cellular Biology

205

192

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Both casein kinase 1 delta (CK1␦) and epsilon (CK1) phosphorylate core clock proteins of the mammalian circadian oscillator. To assess the roles of CK1␦ and CK1 in the circadian clock mechanism, we generated mice in which the genes encoding these proteins (Csnk1d and Csnk1e, respectively) could be disrupted using the Cre-loxP system. Cre-mediated excision of the floxed exon 2 from Csnk1d led to in-frame splicing and production of a deletion mutant protein (CK1␦ ⌬2 ). This product is nonfunctional. Mice homozygous for the allele lacking exon 2 die in the perinatal period, so we generated mice with liver-specific disruption of CK1␦. In livers from these mice, daytime levels of nuclear PER proteins, and PER-CRY-CLOCK complexes were elevated. In vitro, the half-life of PER2 was increased by ϳ20%, and the period of PER2::luciferase bioluminescence rhythms was 2 h longer than in controls. Fibroblast cultures from CK1␦-deficient embryos also had long-period rhythms. In contrast, disruption of the gene encoding CK1 did not alter these circadian endpoints. These results reveal important functional differences between CK1␦ and CK1: CK1␦ plays an unexpectedly important role in maintaining the 24-h circadian cycle length.Circadian rhythms are rhythms in gene expression, metabolism, physiology, and behavior that persist in constant environmental conditions with a cycle length near 24 h. In mammals, the circadian timing system is hierarchical. The primary pacemaker regulating circadian behavioral rhythms is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Most cell types express circadian clock genes and will express rhythmicity in vitro. In vivo, the SCN entrains peripheral oscillators through a complex set of physiological and hormonal rhythms (31,32,36).At the molecular level, circadian oscillations are governed by a cell-autonomous negative-feedback loop in which transcription factors drive the expression of their own negative regulators, leading to oscillation between periods of transcriptional activation and repression (reviewed in references 32 and 36). The bHLH-PAS containing transcription factors CLOCK or NPAS2 form heterodimers with BMAL1. These heterodimers binds to E-box elements within regulatory regions of Period (Per1, Per2, and Per3) and Cryptochrome (Cry1 and Cry2) genes to stimulate their transcription. Approximately 12 h after transcriptional activation, PER and CRY proteins reach concentrations sufficient to form repressor complexes that inhibit the activity of the CLOCK/NPAS2:BMAL1 heterodimer, reducing the transcription of Per and Cry genes and subsequently relieving PER/CRY-mediated negative feedback. E-box-mediated expression of other transcription factors, including members of the DBP/HLF/TEF and nuclear orphan receptor families (e.g., Rev-Erb␣ and ROR-A), provides a mechanism for clock control of genes with diverse promoters and with gene expression peaks occurring at a variety of phases.Posttranslational modifications of circadian clock proteins play a well-established role in the re...

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Constitutive expression of thePeriod1gene impairs behavioral and molecular circadian rhythms

Cited by 60 publications

References 41 publications

Probing the Relative Importance of Molecular Oscillations in the Circadian Clock

Probing the Relative Importance of Molecular Oscillations in the Circadian Clock

The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

Casein Kinase 1 Delta Regulates the Pace of the Mammalian Circadian Clock

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