double-time Is a Novel Drosophila Clock Gene that Regulates PERIOD Protein Accumulation

Price, Jeffrey L.; Blau, Justin; Rothenfluh, Adrian; Abodeely, Marla; Kloss, Brian; Young, Michael W.

doi:10.1016/s0092-8674(00)81224-6

Cited by 744 publications

(719 citation statements)

References 55 publications

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“…52 In addition, the PAR-leucine zipper transcription factor albumin D element-binding protein (DBP) is a first-order clock-controlled gene directly regulated by BMAL1/ CLOCK; 53 it also plays a role in the core clock by activating Per1 transcription. 54 Kinases such as CKId, 55,56 CKIe 57,58 and GSK3b 25,59 play an important role in phosphorylation of clock proteins, thus regulating the activity, nuclear entry and degradation of various core clock components. Among these kinases, GSK3b is of particular interest here because it was reported to be one of the direct targets of lithium, 60 which is an effective therapy for bipolar disorder.…”

Section: Introductionmentioning

confidence: 99%

Assessment of circadian function in fibroblasts of patients with bipolar disorder

et al. 2008

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Previous studies have implicated the circadian system in the pathophysiology of bipolar disorder, but conclusive evidence for altered circadian clocks is lacking. Cultured fibroblasts harbor circadian clocks representative of those in the master clock resident in the suprachiasmatic nuclei, providing a new avenue to investigate the core clock machinery in patients with bipolar illness. We examined the rhythmic expression patterns of core clock genes (BMAL1, PER1, PER2, REV-ERBa, DEC2, DBP) in fibroblasts from 12 bipolar patients and 12 healthy controls. Although we did not detect differences in the circadian period between bipolar patients and controls, the amplitude of rhythmic expression for BMAL1, REVERBa and DBP, as well as the overall mRNA expression level for DEC2 and DBP was reduced in fibroblasts from bipolar patients. Bonferroni's correction for multiple comparisons still resulted in significantly reduced DBP expression level, and trends toward reduced overall expression level of DEC2 and circadian amplitude of BMAL1, in fibroblasts from bipolar patients. We next examined an expanded cohort of 18 bipolar patients and 35 healthy controls for mRNA expression levels of four kinases (CKId, CKIe, GSK3a and GSK3b) and the protein and phosphorylation levels of two of them (GSK3a and GSK3b). We did not detect differences in steady-state mRNA levels or protein levels of these kinases between bipolar patients and controls, but the level of GSK3b phosphorylation was significantly reduced in bipolar patients within an Old Order Amish bipolar kindred. Our results suggest that the reduced amplitudes and overall expression levels of circadian genes, and the decreased phosphorylation level of GSK3b may lead to dysregulation of downstream genes, which could explain some pathological features of bipolar disorder.

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Section: Introductionmentioning

confidence: 99%

Assessment of circadian function in fibroblasts of patients with bipolar disorder

et al. 2008

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“…Posttranscriptional regulation and even posttranslational regulation also contribute to the TTFL (9)(10)(11)(12). In addition, there are substantial differences between the expression levels and the cycling patterns of nascent and mature transcripts (9,13).…”

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confidence: 99%

mir-276a strengthens Drosophila circadian rhythms by regulating timeless expression

Xiao

Rosbash

2016

Proc. Natl. Acad. Sci. U.S.A.

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Circadian rhythms in metazoan eukaryotes are controlled by an endogenous molecular clock. It functions in many locations, including subsets of brain neurons (clock neurons) within the central nervous system. Although the molecular clock relies on transcription/translation feedback loops, posttranscriptional regulation also plays an important role. Here, we show that the abundant Drosophila melanogaster microRNA mir-276a regulates molecular and behavioral rhythms by inhibiting expression of the important clock gene timeless (tim). Misregulation of mir-276a in clock neurons alters tim expression and increases arrhythmicity under standard constant darkness (DD) conditions. mir-276a expression itself appears to be light-regulated because its levels oscillate under 24-h light-dark (LD) cycles but not in DD. mir-276a is regulated by the transcription activator Chorion factor 2 in flies and in tissue-culture cells. Evidence from flies mutated using the clustered, regularly interspaced, short palindromic repeats (CRISPR) tool shows that mir-276a inhibits tim expression: Deleting the mir276a-binding site in the tim 3′ UTR causes elevated levels of TIM and ∼50% arrhythmicity. We suggest that this pathway contributes to the more robust rhythms observed under light/dark LD conditions than under DD conditions. microRNA | circadian rhythms | light regulation | CRISPR

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“…(3) Circadian rhythms are robust and easily quantifiable at the single fly level. This allowed screens of single F 1 progeny [23] rather than having to generate lines of fliesand the same approach was successful in identifying clock mutations in mice [24]. (4) Functional clocks in Drosophila are found not only in the pacemaker cells in the brain that drive behavioural rhythms but also in peripheral oscillators in sensory neurons (e.g.…”

Section: Circadian Rhythms In Drosophilamentioning

confidence: 99%

“…SGG overexpression leads to hyperphosphorylated TIM and the PER/TIM heterodimer translocates into the nucleus ∼4 h early, shortening the period as CLK/CYC activity is inhibited prematurely [30]. Many other factors contribute to this loop, including DOUBLE-TIME (DBT), a Casein Kinase Iɛ homologue [23], Casein Kinase II [31,32], Protein Phosphatase 2A (PP2A) [33], the F-box protein SLIMB [34,35], and the blue light photoreceptor CRYPTOCHROME (CRY), that also doubles as a transcriptional repressor in some clock cells [26,36,37]. Attention has largely focussed on how these proteins regulate the stability of PER and TIM, although DBT and PP2A also regulate CLK activity [38], with hypophosphorylated CLK associated with maximal per transcription [29,38].…”

Section: The Drosophila Molecular Clockmentioning

confidence: 99%

Even a stopped clock tells the right time twice a day: circadian timekeeping in Drosophila

Collins

Blau

2007

Pflugers Arch - Eur J Physiol

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"Even a stopped clock tells the right time twice a day, and for once I'm inclined to believe Withnail is right. We are indeed drifting into the arena of the unwell... What we need is harmony. Fresh air. Stuff like that." Bruce Robinson (1986, ref. 1). Although a stopped Drosophila clock probably does not tell the right time even once a day, recent findings have demonstrated that accurate circadian time-keeping is dependent on harmony between groups of clock neurons within the brain. Furthermore, when harmony between the environment and the endogenous clock is lost, as during jet lag, we definitely feel unwell. In this review, we provide an overview of the current understanding of circadian rhythms in Drosophila, focussing on recent discoveries that demonstrate how approximately 100 neurons within the Drosophila brain control the behaviour of the whole fly, and how these rhythms respond to the environment.

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double-time Is a Novel Drosophila Clock Gene that Regulates PERIOD Protein Accumulation

Cited by 744 publications

References 55 publications

Assessment of circadian function in fibroblasts of patients with bipolar disorder

Assessment of circadian function in fibroblasts of patients with bipolar disorder

mir-276a strengthens Drosophila circadian rhythms by regulating timeless expression

Even a stopped clock tells the right time twice a day: circadian timekeeping in Drosophila

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