A mammalian ortholog of <i>Drosophila timeless</i>, highly expressed in SCN and retina, forms a complex with mPER1

Takumi, Toru; Nagamine, Yasuko; Miyake, Shigeru; Matsubara, Chiaki; Taguchi, Kouji; Takekida, Shigeki; Sakakida, Yoko; Nishikawa, K.; Kishimoto, Toshihiko; Niwa, Shin-ichiro; Okumura, Katsuhiko; Okamura, Hitoshi

doi:10.1046/j.1365-2443.1999.00238.x

Cited by 70 publications

(53 citation statements)

References 35 publications

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“…The transcription of the mCry1 gene in the SCN exhibits a circadian oscillation (7) comparable to those of other circadian genes including mPer1 (127,128), mPer2 (133,134), mPer3 (129,135), and mTim (130,136). The mCry1 mRNA level reaches a maximum at ZT 6-8 (ZT = 0 by convention, the time at which the light is turned on) and declines to a minimum at ZT 24 ( Figure 8).…”

Section: Circadian Oscillation Of Cryptochrome Expressionmentioning

confidence: 89%

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Cryptochrome: The Second Photoactive Pigment in the Eye and Its Role in Circadian Photoreception

Sancar

2000

Annu. Rev. Biochem.

243

201

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Key Words blue-light photoreceptor, flavoprotein, retina, suprachiasmatic nucleus, circadian blind mice, seasonal affective disorder s Abstract Circadian rhythms are oscillations in the biochemical, physiological, and behavioral functions of organisms that occur with a periodicity of approximately 24 h. They are generated by a molecular clock that is synchronized with the solar day by environmental photic input. The cryptochromes are the mammalian circadian photoreceptors. They absorb light and transmit the electromagnetic signal to the molecular clock using a pterin and flavin adenine dinucleotide (FAD) as chromophore/cofactors, and are evolutionarily conserved and structurally related to the DNA repair enzyme photolyase. Humans and mice have two cryptochrome genes, CRY1 and CRY2, that are differentially expressed in the retina relative to the opsin-based visual photoreceptors. CRY1 is highly expressed with circadian periodicity in the mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN). Mutant mice lacking either Cry1 or Cry2 have impaired light induction of the clock gene mPer1 and have abnormally short or long intrinsic periods, respectively. The double mutant has normal vision but is defective in mPer1 induction by light and lacks molecular and behavioral rhythmicity in constant darkness. Thus, cryptochromes are photoreceptors and central components of the molecular clock. Genetic evidence also shows that cryptochromes are circadian photoreceptors in Drosophila and Arabidopsis, raising the possibility that they may be universal circadian photoreceptors. Research on cryptochromes may provide new understanding of human diseases such as seasonal affective disorder and delayed sleep phase syndrome. CONTENTS

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Section: Circadian Oscillation Of Cryptochrome Expressionmentioning

confidence: 89%

“…Currently, the known components of the molecular oscillator in mice are CLOCK (126,151), BMAL1 (131,132), PER1, PER2, PER3 (127)(128)(129)(132)(133)(134)(135), and TIM (129,130,136). The expression patterns of Per1, 2, and 3 show robust circadian oscillation in the SCN and peripheral tissues.…”

Section: Status Of the Molecular Clock In Cryptochrome Mutant Micementioning

confidence: 99%

Cryptochrome: The Second Photoactive Pigment in the Eye and Its Role in Circadian Photoreception

Sancar

2000

Annu. Rev. Biochem.

243

201

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“…Conflicting reports exist regarding cycling of Tim RNA in the SCN of mice, and studies reveal no oscillation or lightresponsiveness of TIM protein in the SCN (61,76). Although TIM has been reported to interact with PER1 in cell culture (195), it does not influence the cellular localization of the PER proteins in immunofluorescence studies (111,207). It does, however, interact with the CRY proteins both in cell culture and in native SCN extracts (61,111).…”

Section: Time Now For Timeless?mentioning

confidence: 99%

“…Included in Table 1 is the gene Timeless, previously reported to be a mammalian ortholog of Drosophila tim (105,170,195,197,232). In flies, TIM and PER heterodimerize, translocate to the nucleus, and inhibit CLOCK:CYCLE-mediated transcription, much like the CRY-PER complexes just described in mammals (7,215).…”

Section: Time Now For Timeless?mentioning

confidence: 99%

MAMMALIAN CIRCADIAN BIOLOGY: Elucidating Genome-Wide Levels of Temporal Organization

Lowrey

Takahashi

2004

Annu. Rev. Genom. Hum. Genet.

868

727

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During the past decade, the molecular mechanisms underlying the mammalian circadian clock have been defined. A core set of circadian clock genes common to most cells throughout the body code for proteins that feed back to regulate not only their own expression, but also that of clock output genes and pathways throughout the genome. The circadian system represents a complex multioscillatory temporal network in which an ensemble of coupled neurons comprising the principal circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus is entrained to the daily light/dark cycle and subsequently transmits synchronizing signals to local circadian oscillators in peripheral tissues. Only recently has the importance of this system to the regulation of such fundamental biological processes as the cell cycle and metabolism become apparent. A convergence of data from microarray studies, quantitative trait locus analysis, and mutagenesis screens demonstrates the pervasiveness of circadian regulation in biological systems. The importance of maintaining the internal temporal homeostasis conferred by the circadian system is revealed by animal models in which mutations in genes coding for core components of the clock result in disease, including cancer and disturbances to the sleep/wake cycle.

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“…Mammals do not have a true ortholog of Drosophila TIM1 but rather have an ortholog of Drosophila Timeout (dTIM2), a gene with no known function in the fly's clock. Mammalian TIM is expressed in the suprachiasmatic nucleus (SCN), the site of the mammalian pacemaker, but there is an ongoing debate concerning its role, if any, in central rhythm generation (Zylka et al 1998;Takumi et al 1999;Field et al 2000;Gotter at al. 2000;Barnes et al 2003).…”

mentioning

confidence: 99%

Molecular and phylogenetic analyses reveal mammalian-like clockwork in the honey bee (Apis mellifera) and shed new light on the molecular evolution of the circadian clock

et al. 2006

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The circadian clock of the honey bee is implicated in ecologically relevant complex behaviors. These include time sensing, time-compensated sun-compass navigation, and social behaviors such as coordination of activity, dance language communication, and division of labor. The molecular underpinnings of the bee circadian clock are largely unknown. We show that clock gene structure and expression pattern in the honey bee are more similar to the mouse than to Drosophila. The honey bee genome does not encode an ortholog of Drosophila Timeless (Tim1), has only the mammalian type Cryptochrome (Cry-m), and has a single ortholog for each of the other canonical "clock genes." In foragers that typically have strong circadian rhythms, brain mRNA levels of amCry, but not amTim as in Drosophila, consistently oscillate with strong amplitude and a phase similar to amPeriod (amPer) under both light-dark and constant darkness illumination regimes. In contrast to Drosophila, the honey bee amCYC protein contains a transactivation domain and its brain transcript levels oscillate at virtually an anti-phase to amPer, as it does in the mouse. Phylogenetic analyses indicate that the basal insect lineage had both the mammalian and Drosophila types of Cry and Tim. Our results suggest that during evolution, Drosophila diverged from the ancestral insect clock and specialized in using a set of clock gene orthologs that was lost by both mammals and bees, which in turn converged and specialized in the other set. These findings illustrate a previously unappreciated diversity of insect clockwork and raise critical questions concerning the evolution and functional significance of species-specific variation in molecular clockwork.

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A mammalian ortholog of Drosophila timeless, highly expressed in SCN and retina, forms a complex with mPER1

Cited by 70 publications

References 35 publications

Cryptochrome: The Second Photoactive Pigment in the Eye and Its Role in Circadian Photoreception

Cryptochrome: The Second Photoactive Pigment in the Eye and Its Role in Circadian Photoreception

MAMMALIAN CIRCADIAN BIOLOGY: Elucidating Genome-Wide Levels of Temporal Organization

Molecular and phylogenetic analyses reveal mammalian-like clockwork in the honey bee (Apis mellifera) and shed new light on the molecular evolution of the circadian clock

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