A rhythmic Ror

Department of Neurobiology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, USA.
Neuron (Impact Factor: 15.05). 09/2004; 43(4):443-6. DOI: 10.1016/j.neuron.2004.08.009
Source: PubMed


The circadian clock mechanism in mammals involves two interlocking transcriptional feedback loops. Rev-erb alpha, through its role as a transcriptional repressor, was thought to be the primary determinant of the feedback loop that regulates Bmal1 transcription. Results reported by Sato et al. in this issue of Neuron now show that the transactivator Rora acts coordinately with Rev-erb alpha and that their competing activities on the same promoter element drive the rhythm in Bmal1 transcription. This finding defines the second feedback loop in mammals.

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Available from: Patrick Emery, Aug 20, 2015
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    • "They are generated by a complex transcriptional network of interlocked feedback loops. The architecture of this network and many of its components are conserved between insects and mammals (Emery & Reppert, 2004). "
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    ABSTRACT: Circadian rhythms are generated by well-conserved interlocked transcriptional feedback loops in animals. In Drosophila, the dimeric transcription factor CLOCK/CYCLE (CLK/CYC) promotes period (per), timeless (tim), vrille (vri), and PAR-domain protein 1 (Pdp1) transcription. PER and TIM negatively feed back on CLK/CYC transcriptional activity, whereas VRI and PDP1 negatively and positively regulate Clk transcription, respectively. Here, we show that the α isoform of the Drosophila FOS homolog KAYAK (KAY) is required for normal circadian behavior. KAY-α downregulation in circadian pacemaker neurons increases period length by 1.5 h. This behavioral phenotype is correlated with decreased expression of several circadian proteins. The strongest effects are on CLK and the neuropeptide PIGMENT DISPERSING FACTOR, which are both under VRI and PDP1 control. Consistently, KAY-α can bind to VRI and inhibit its interaction with the Clk promoter. Interestingly, KAY-α can also repress CLK activity. Hence, in flies with low KAY-α levels, CLK derepression would partially compensate for increased VRI repression, thus attenuating the consequences of KAY-α downregulation on CLK targets. We propose that the double role of KAY-α in the two transcriptional loops controlling Drosophila circadian behavior brings precision and stability to their oscillations.
    Full-text · Article · Nov 2012 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    • "After translation, dimerization, and translocation to the nucleus, the Per and Cry proteins physically interact with and thereby inhibit the transcriptional activation driven by the Clock: Bmal complex. Further, an additional feedback loop directs the rhythmic expression of the bmal transcript (Emery and Reppert, 2004). The presence of this additional loop together with the tightly regulated stability, turn over, and subcellular localization of core clock components all contribute to conferring accuracy and robustness on the clock mechanism. "
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    ABSTRACT: Our understanding of the molecular and cellular organization of the circadian timing system in vertebrates has increased enormously over the past decade. In large part, progress has been based on genetic studies in the mouse as well as on fundamental similarities between vertebrate and Drosophila clocks. The zebrafish was initially considered as a potentially attractive genetic model for identifying vertebrate clock genes. However, instead, fish have ultimately proven to be valuable complementary models for studying various aspects of clock biology. For example, many fish can shift from diurnal to nocturnal activity implying specific flexibility in their clock function. We have learned much about the function of light input pathways, and the ontogeny and function of the pineal organ, the fish central pacemaker. Finally, blind cavefish have also provided new insight into the evolution of the circadian clock under extreme environmental conditions.
    Full-text · Article · Aug 2012 · Progress in brain research
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    • "Another factor that can interact with autoregulatory feedback loops of circadian clocks, which interestingly also responds to melatonin, is the transcriptional factor Rorα, a member of the RZR/ROR nuclear receptor family. It has been demonstrated that RORα binds to ROREs (retinoic acid receptor–related orphan receptor response element) in E-box sequences and activates transcriptional processes of some circadian genes (Emery & Reppert, 2004). "
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    ABSTRACT: Melatonin, the pineal gland hormone, provides entrainment of many circadian rhythms to the ambient light/dark cycle. Recently, cardiovascular studies have demonstrated melatonin interactions with many physiological processes and diseases, such as hypertension and cardiopathologies. Although membrane melatonin receptors (MT1, MT2) and the transcriptional factor RORα have been reported to be expressed in the heart, there is no evidence of the cell-type expressing receptors as well as the possible role of melatonin on the expression of the circadian clock of cardiomyocytes, which play an important role in cardiac metabolism and function. Therefore, the aim of this study was to evaluate the mRNA and protein expressions of MT1, MT2, and RORα and to determine whether melatonin directly influences expression of circadian clocks within cultured rat cardiomyocytes. Adult rat cardiomyocyte cultures were created, and the cells were stimulated with 1 nM melatonin or vehicle. Gene expressions were assayed by real-time polymerase chain reaction (PCR). The mRNA and protein expressions of membrane melatonin receptors and RORα were established within adult rat cardiomyocytes. Two hours of melatonin stimulation did not alter the expression pattern of the analyzed genes. However, given at the proper time, melatonin kept Rev-erbα expression chronically high, specifically 12 h after melatonin treatment, avoiding the rhythmic decline of Rev-erbα mRNA. The blockage of MT1 and MT2 by luzindole did not alter the observed melatonin-induced expression of Rev-erbα mRNA, suggesting the nonparticipation of MT1 and MT2 on the melatonin effect within cardiomyocytes. It is possible to speculate that melatonin, in adult rat cardiomyocytes, may play an important role in the light signal transduction to peripheral organs, such as the heart, modulating its intrinsic rhythmicity.
    Full-text · Article · Feb 2011 · Chronobiology International
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