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1 Department of Physiology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
2 Department of Oral Functional Science, Hokkaido University Graduate School of Dentistry, Sapporo 060-8586, Japan
3 Research Institute for Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Midorigaoka, Ikeda, Osaka 563-8577, Japan
4 Molecular Clock Project, Research Center for Genomic Medicine, Saitama Medical School, Hidaka, Saitama 350-1241, Japan
5 Department of Physiology, Saitama Medical School, Moroyama, Saitama 350-0495, Japan
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Abstract |
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Introduction |
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TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
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A real time monitoring technique of gene expression was successfully introduced to the field of circadian rhythm research in mammals and has enabled us to measure promoter activity of a clock gene for a long-term with bioluminescence, not only in vitro but also in vivo (Yamazaki et al. 2000; Yamaguchi et al. 2001; Wilsbacher et al. 2002; Yoo et al. 2004). A reporter gene coding a luciferase is connected to the downstream of a clock gene promoter region, and transfected to mice or rats to produce transgenic animals carrying a clock gene reporter system.
Circadian rhythms of clock gene expression in peripheral tissues damped out in several cycles, and, therefore, have been regarded as regulated by damped oscillations (Yamazaki et al. 2000). On the other hand, circadian rhythms in the SCN seem to persist in vitro as long as the SCN tissue is viable. Recently, Yoo et al. (2004) demonstrated that circadian rhythms in protein products of Per2 persisted for more than 20 cycles in mouse cultured livers and lungs, and suggested that the peripheral clocks were also self-sustained as the master clock in the SCN. Long-term persistence of circadian rhythms in peripheral tissues is strong evidence for existence of mutual coupling among cellular rhythms. In this respect, recent findings by Balsalobre et al. (1998) and Nagoshi et al. (2004) are important to understanding the coupling mechanism of cellular oscillations. They demonstrated that dexamethazone synchronized cellular rhythms instantaneously by using type 0 resetting properties of individual circadian oscillations.
To our knowledge, a reporter system so far published is restricted to Per families (Yamazaki et al. 2000; Yamaguchi et al. 2001; Wilsbacher et al. 2002; Yoo et al. 2004). Bmal1, a positive element of an auto-feedback circadian loop, shows robust rhythms in its expression in the peripheral tissues such as the liver, kidney and heart as well as in the SCN (Honma et al. 1998; Oishi et al. 1998; Lee et al. 2001; Yamamoto et al. 2004). Noteworthy is the robustness of Bmal1 expression rhythms in peripheral tissues, which are comparable with Per(s) expression rhythms in the SCN, suggesting a different role for Bmal1 in the peripheral circadian oscillation. Here, we developed a new reporter system for monitoring the expression of two clock genes, Per1 and Bmal1, from a single tissue in mice. DNA coding firefly luciferase (FL) was fused to downstream of a promoter region of mouse (m)Bmal1, and DNA coding Vargula hilgendorfii luciferase (VL) to a promoter region of mPer1 (Fig. 1A). Transgenic mice carrying Per1-VL and Bmal1-FL (PVBF-mice) were obtained. Reporters are VL, a secreting protein (Thompson et al. 1989; Inouye et al. 1992; Tanahashi et al. 2001) measured in culture medium collected sequentially, and FL, a non-secreting one measured in real time. They increase in parallel with Per1 and Bmal1 expressions, respectively.
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Results |
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Formal properties of circadian rhythm in spontaneous locomotor activity were obtained in PVBF mice. Free-running period (24.00 ± 00.01 h; mean ± SD) and activity time (14.3 ± 0.6 h) in constant darkness (DD) was not significantly different from their respective parameters of the wild-type (Fig. 1B). They responded to a single light pulse of 30 min in DD with a phase-delay shift of 2.3 ± 0.5 h at circadian time (CT)14 and a phase-advance shift of 1.1 ± 0.6 h at CT22, which were not significantly different from those of the wild-type. Circadian rhythms in three clock gene expressions, Per1, Per2, and Bma1l, in the suprachiasmatic nucleus (SCN) of PVBF mice were not significantly different from those of wild-type (two way ANOVA) (Fig. 1C). These findings indicate that the circadian system of PVBF mice is not significantly different from that of wild-type. A correlation was not detected between the time of slice preparation and the circadian peak.
Determination of circadian rhythms in Bmal1-FL and Per1-VL from a single SCN
Activities of Bmal1-FL were determined in real time from a single cultured SCN tissue, and activities of Per1-VL in culture medium at 4 h intervals for 36 h. Per1 expression in terms of VL activity exhibited a clear circadian rhythm with a peak at Zeitgeber time (ZT)10
14, whereas Bmal1 expression in terms of FL activity showed a robust circadian rhythm with a peak at ZT20.4 ± 1.3 (n = 3), where time of light-on in LD cycles was defined as ZT0. The two rhythms were almost 180 degree out of phase (Fig. 2). The circadian peak in Bmal1-FL rhythm was phase delayed by 4–6 h when compared with the peak of Bmal1 mRNA rhythm (Fig. 1C). Similarly, the circadian peaks in Per1-VL rhythm were phase delayed by 6–8 h when compared with the peak of Per1 mRNA rhythm.
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Robust circadian rhythms in Bmal1-FL were detected in peripheral tissues such as the eye, lung, heart, aorta, diaphragm, stomach, liver, kidney, and testis (Fig. 3A). The circadian peaks in peripheral tissues were located at different times of day (Fig. 3B left), which were significantly different from the circadian peak in the SCN (ZT20.1 ± 1.4 h), except for the eye. The lung, aorta, diaphragm, liver, and kidney showed the circadian phases at transition from dark to light in LD (a 12-h light/12-h dark cycle). In the stomach and testis, circadian peaks were located at ZT12.6 h and ZT14.8 h, respectively, which were almost anti-phasic to most of other peripheral rhythms examined. Inter-individual difference in the peak phase was also large in these tissues.
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Circadian rhythms in Bmal1-FL persisted in the liver for more than 3 weeks keeping a stable steady-state circadian period (Fig. 4A). The circadian period was shorter in the first few cycles as mentioned already. In some tissues, the circadian rhythms seemed to damp out in the course of culture, but were restored by refreshment of culture medium. The renewed circadian rhythms were located almost on the same track as they had been previously, regardless of where in the circadian cycle medium exchange was done (Figs 4B and 5A). Refreshment of culture medium, however, affected the phase of circadian rhythm, the magnitude and direction of which depended on the phase where medium exchange was carried out. Phase advance shifts of 4 h were observed at around the circadian peak, and phase-delay shifts of 3 h at around the circadian trough of Bmal1-FL, respectively. Transitions from phase-delay shift to phase-advance and vice versa were located at two circadian phases between the peak and trough (Fig. 5B).
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Discussion |
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As demonstrated in Fig. 2, circadian rhythms in Bmal1-FL and Per1-VL in the SCN are almost anti-phasic. Antiphasic relationship has been repeatedly observed in the circadian rhythms of Bmal1 and Per1 expressions in the mouse SCN (Oishi et al. 1998; Abe et al. 2001; Okano et al. 2001). However, the circadian phase of Bmal1-FL in the present study was delayed by 4–6 h when compared with that in Bmal1 mRNA levels (Fig. 1C). The delay of circadian phase in FL reporter seems to be intrinsic to any reporter system using bioluminescence, because of a lapse of several hours required for protein, luciferase (FL), synthesis from its mRNA. The same seems to be true for circadian rhythms in Per1-VL. The circadian phase in VL reporter was delayed by 6–8 h when compared with that in Per1 mRNA levels. A few more hours are required to produce and secrete the reporter proteins (Tanahashi et al. 2001). The phase delay, however, is easily adjusted.
The present study provided the first observation of Bmal1 expression in real time in various tissues including the SCN. As demonstrated in Fig. 3B, the circadian peaks and periods in most peripheral tissues were significantly different from those in the SCN and from each other. Similar differences in the circadian phase were observed previously in the assessment of Per gene expression by a firefly luciferase reporter system (Yamazaki et al. 2002; Davidson et al. 2003; Yoo et al. 2004). On the other hand, the peak circadian phases in Bmal1 mRNA were not much different among tissues in the previous studies (Oishi et al. 2004; Yamamoto et al. 2004).
Effects of preparation time on the phase of cultured tissues were recently reported in Per1-luc expression rhythm (Yoshikawa et al. 2005). When the tissues were prepared in the dark or early light period (at ZT17, 23 or 1), the peak phase was delayed by 6 h from per1 mRNA rhythm as determined by in situ hybridization, and when prepared at ZT2 and ZT14, the peak showed intermediate delay-shifts. On the other hand, when the preparation was done during the middle of the light period (at ZT5 and ZT11), no phase shift was detected. We did not observe such effects of preparation time on the phase of Bmal1 expression rhythm, probably because we prepared culture tissues during the middle of light period (ZT4 to ZT11). There was no correlation between the preparation time and the Bmal1 expression peak in cultured tissues. Furthermore, a difference in the peak phase was observed among tissues from a single animal. Therefore, differences in the peak phases among peripheral tissues detected in the present study were unlikely to be due to the differences in sampling time.
The reasons are not known why circadian peaks in the stomach and testis are substantially different from other peripheral tissues. It is well known that different organs exert their maximum functions at different time of day. For instance, in nocturnal rodents, the circadian rhythm in serum gastrin peaks at the middle of dark phase (Oscarson et al. 1979). On the other hand, the circadian rhythm in plasma testosterone peaks at the early light phase (Grotjan & Johnson 1976), whereas spermatogenesis does not show clear circadian rhythms (Oakberg et al. 1986). The circadian rhythm in plasma corticosterone, a possible endogenous zeitgeber for the liver (Balsalobre et al. 2000), peaks at the late light phase (Honma & Hiroshige 1978). Although we do not know the exact mechanisms by which the circadian rhythms in these organs are reset, their phase positions under light entrainment might be determined by the SCN through different internal mediators (zeitgebers) which also show circadian rhythms.
The circadian periods in the liver and testis were shorter than the period in the SCN. In the liver, the period became longer in a first few cycles and reached a steady state value. The finding suggests that some metabolic process is involved in determination of the period length, since the liver is metabolically active and seems to require several days to adapt to culture conditions.
Conflicting reports were published on circadian rhythms in the testis (Zylka et al. 1998; Alvarez et al. 2003; Morse et al. 2003; Yamamoto et al. 2004). As demonstrated in Fig. 3A, Bmal1-FL showed robust circadian rhythms in mouse testis, although there was a large interindividual difference in the circadian peak. A failure of previous reports to demonstrate circadian rhythms in the testis (Alvarez et al. 2003; Morse et al. 2003) might be partly due to a large interindividual difference in circadian phase.
The Bmal1-FL reporter system enabled us to monitor circadian rhythms in the liver for more than 3 weeks. Previously, circadian rhythms in peripheral tissues were regarded as damping oscillation, because of a rapid decrease in the circadian amplitude (Yamazaki et al. 2000). Yoo et al. (2004), suggested existence of self-sustained oscillations in the peripheral tissues by demonstrating persistence of circadian rhythms in a PER2 reporter for more than 20 cycles. In the present study, circadian rhythms in bioluminescence damped out apparently in the course of culture, but this does not seem to be real damping of the circadian oscillation. Because, the circadian rhythms were restored after refreshment of the culture medium and persisted for more than 2 weeks thereafter. The restored circadian rhythms were located on almost the same track as they had been previously. The restoration is unlikely to be due to the restart of the circadian rhythm. Apparent damping observed in the circadian rhythm of FL activity can be explained by a failure of the luciferin–luciferase reaction in the cells due to impoverishment of the medium conditions.
Recently, Nagoshi et al. (2004) indicated that circadian rhythms in rat fibroblasts induced by serum shock were not due to de novo operation of a circadian feedback loop (oscillation), but due to resynchronization of already desynchronized constitutional cellular rhythms. They succeeded in demonstrating a type 0 phase response curve (PRC) in cultured cells, which was a requirement for instantaneous resetting of desynchronized circadian rhythms (Pittendrigh 1967). Individual cell oscillations are instantaneously reset by serum shock at whatever circadian phases they used to be, and circadian rhythm in populations appears. Such instantaneous resetting is a possible mechanism of phase adjustment of peripheral rhythms by the SCN. In the liver, refreshment of culture medium produced a phase-dependent phase shift in circadian rhythms of Bmal1-FL (Fig. 5B). However, a PRC obtained for a single medium exchange was not type 0. Although PRC shapes of individual cell oscillations are not known, instantaneous resetting seems to be difficult by this PRC. Thus, circadian oscillations in cultured liver tissues are resistant to external perturbations probably because cell architecture is preserved in the liver slices. The cell to cell communication may play an important role in the response of the circadian system to zeitgebers. The present result together with the previous report challenges the concept of damping oscillations in the peripheral tissue, and supports an idea that peripheral rhythms are also self-sustained as is the case of the SCN circadian rhythms (Yoo et al. 2004).
Unexpected was a finding of ultradian rhythm with a period of c. 8 h detected in the liver. Ultradian rhythms appeared and disappeared each by medium exchange. The mechanism of switch from circadian to ultradian and vice versa in not known. It is interesting to note that the circadian rhythms that reappeared were located on the same track as they had been previously, suggesting persistence of the circadian oscillation during the period of ultradian dominancy. It is not known whether ultradian rhythms were an artifact of the reporter system, or expression of biological processes in the liver.
In conclusion, using a new reporter system for monitoring of Bmal1 and Per1 expressions, we were able to demonstrate circadian oscillations in the peripheral tissues such as the liver, which persisted for more than 3 weeks without changing their periods and responded slightly but systematically to external perturbations. The findings strongly suggest that the peripheral clocks consist of self-sustained oscillators similarly to the central clock in the SCN. It remains, however, to be elucidated how the peripheral clocks operate stable circadian oscillations.
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Experimental procedures |
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From Bp/8096 LUC vector (Yu et al. 2002), Bmal1-FL cassette was excised with SalI, which contained 8.1 kbp of mBmal1 5' flanking region (–7994
+99), firefly luciferase (FL) coding region and simian virus 40 polyadenylation signal. The cassette was inserted into the SalI/XhoI site of cloning vector pMCS5 (MoBitec GmbH, Goettingen, Germany), resulting in pBmal1-FL. To make a Per1-VL cassette, a 6.8 kbp of 5' flanking region of mPer1 promoter (–5053
+1294) was amplified by PCR from mPer1-FL reporter vector pL18 (provided by Dr H. Tei, Hida et al. 2000) using mPer1-F-NruI (5'-TCGCGAGATCCGATGCCCTCTTCTGGTGT-3') and mPer1-R-EcoRI (5'-GAATTCACCACTCTTGTCTGGGCCATACA-3'). The amplified product was ligated into the NruI/EcoRI site of expression vector pcDNA3 (Invitrogen, Carlsbad, CA, USA), resulting in pPer1-pcDNA3 from which the cytomegalovirus promoter had been removed. The VL coding region (Thompson et al. 1989) was PCR amplified from expression vector pcDNA-VL (Nakajima et al. 2004) using VL-F-NotI (5'-GCGGCCGCATGAAGATAATAATTCTGTCTG-3') and VL-R-NotI (5'-GCGGCCGCTTATTGACATTCAGGTGGTACT-3'), and the amplified product was ligated into the NotI site downstream of the mPer1 promoter of pPer1-pcDNA3 to make pPer1-VL. From pPer1-VL, a Per1-VL cassette contained mPer1 promoter, VL coding region and bovine growth hormone polyadenylation signal was further PCR-amplified using pcDNA3-F-MluI (5'-ACGCGTCTGCTCTGATGCCGCATAGTTAAG-3') and pcDNA3-R-AscI (5'-GGCGCGCCAGGGATGCCCCGATTTAGAGCTTGA-3'). The product was ligated into the MluI/AscI site of pBmal1-FL, resulting in pPer1-VL-Bma1l-FL reporter vector. To generate transgenic mice, the vector was linearized by using SalI and AscI (Fig. 1A).
Generation of PVBF transgenic mice
We generated transgenic mice of C57BL/6 J background, PVBF, carrying Per1-VL-Bmal1-FL as a reporter of two clock genes. Among 11 transgenic lines obtained, we selected a PVBF205-4 mouse line expressing FL and VL at high levels. Genotyping was done by PCR to detect the 1.6 kbp coding region of FL (FL forward primer, 5'-GCCACCATGGAAGACGCCAAAAACAT-3' FL reverse primer, 5'-TCCGCCCTTCTTGGCCTTTATGA-3'), using tail genomic DNA.
Phenotypes for FL and VL luciferases were identified by bioluminescence from tail extract. Fifty microliters of extract was added to 50 µL of firefly luciferin (Pica Gene, Toyo Ink) or Vargula luciferin in each well of 96-well luminoplate, and bioluminescence from extract was immediately measured using a luminometer ( JNP-2000, ATTO). The intensity of bioluminescence was 10–100 times higher for VL, and 100–2000 times higher for FL in the transgenic mice than the wild type. Therefore, it was possible to identify the transgenic mice by measuring of FL bioluminescence, which we actually did.
The PVBF205-4 mice were born and reared in our animal quarters where environmental conditions were controlled: temperature (22 ± 2 °C), humidity (60 ± 5%) and a 12-h light/12-h dark cycle (LD; lights on from 06:00 to 18:00 h). Light intensity at the surface of the cages was about 100 lx. They were fed commercial chow and water available all the time. Animals were cared for according to the Guidelines for the Care and Use of Laboratory Animals at Hokkaido University School of Medicine.
Measurement of spontaneous locomotor activity
At 11–16 weeks of age, PVBF205-4 and wild-type male mice (n = 10 for each genotype) were transferred into individual cages in light tight boxes (light intensity in the light phase was 300 lx). Spontaneous locomotor activity was measured by thermal sensor. Mice were kept in LD for 14 days and released into DD. Then a single light pulse of 30 min (300 lx) was given at CT14 on day 24 and at CT22 on day 50 in DD, where activity onset was designated as CT12. Activity values were recorded every min by a PC system (Stanford Chronokit, Stanford Software Systems) and analyzed by Clock Labo (Actimetrix). Magnitude of steady-state phase shift was determined as previously described (Honma et al. 1985). The free-running period was calculated from actograph between day 64 and day 84 in DD by using a 
2 periodogram.
In situ hybridization
PVBF (n = 24) and wild-type mice (n = 24) were decapitated at 4-h intervals in LD. Brain sampling and determination of mPer1, mPer2 and mBmal1 mRNA levels by in situ hybridization were performed as reported previously (Honma et al. 1998; Abe et al. 2004). Optical density was normalized by subtracting signal strength of the corpus callosum in each section and standardized with 14C-acrylic standards (SOD:kBq/g). The average SOD of five SCN sections weighted by area measured represented individual value.
Measurement of Bmal1-FL activity in SCN and peripheral tissues
PVBF205-4 mice were decapitated between ZT4 and 11, where ZT0 is the time of light-on. Peripheral tissues as well as brains were rapidly removed and were placed in ice-cold Hanks’ balanced salt solution (pH 7.4, Sigma). Coronal brain slices of 300 µm thick were prepared using a Microslicer (Dosaka, Osaka, Japan), and a paired SCN were dissected using a surgical knife. Peripheral tissues from the liver, lung, heart, aorta, kidney, and stomach were prepared in slices of 300 µm thick with a Tissue chopper (McIlwain Tissue chopper, The Mickle Laboratory, Surrey, UK). Diaphragm and testis were cut into fragments. Each tissue fragment and enucleated eyeball were explanted on a culture membrane (Millicell CM, pore size 0.4 µm, Millipore) in a 35 mm Petridish sealed with Parafilm (American Can Co., Greenwich) and cultured with 1.3 mL DMEM (Gibco-Invitrogen) supplemented with NaHCO3 (2.7 mM), HEPES (10 mM), Kanamycin (20 mg/L, Gibco), Insulin (5 µg/mL, Sigma), Putrescine (100 mM, Sigma), human Transferrin (100 mg/mL, Sigma), Progesterone (20 nM, Sigma), Sodium Selenite 30 nM (Gibco) and 0.1 mM D-Luciferin K salt (DOJINDO). The cultures were incubated at 37 °C, and bioluminescence was monitored for 1 min at 10 min intervals with a dish type luminometer (AB2500 Kronos, ATTO).
Measurement of Per1-VL activity from a cultured single SCN
Each SCN slice was explanted on a culture membrane (Millicell CM 
12 mm, Millipore) in a 16 mm Petridish and cultured with 0.2 mL medium as indicated above. Bioluminescence by Bmal1-FL was continuously monitored with Kronos. For Per1-VL activity measurement, culture medium was collected every 4 h starting from ZT2 on day1 for 36 h. Before a series of medium samplings, explants were rinsed twice in order to remove VL from a culture dish. Sampling of Per1-VL was performed by collecting the whole medium and replacing it with fresh medium. Per1-VL activity was assayed by adding 50 µL of 50 µM VL luciferin into 50 µL of medium in 96 well luminoplate and by immediately measuring bioluminescence for 20 s with a luminometer (JNP-2000, ATTO).
Analysis of circadian rhythms in bioluminescence
Circadian rhythms in Bmal1-FL were smoothed by a 5 point moving average method, and the peak phases were calculated after subtracting the trends of basal levels. A trend line was obtained by connecting two consecutive troughs in a circadian cycle. The trend line was shifted toward the peak and a point of contact with the bioluminescence curve was defined as the peak phase of the cycle. Circadian period was determined measuring a peak interval.
Statistics
Circadian variation of mRNA levels in the SCN was evaluated by one-way ANOVA, and two groups of time series data were analyzed by two-way ANOVA. Significant difference between two groups was analyzed using Student t-test. All analysis was done using Stat View (SAS Institute Inc.).
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Footnotes |
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* Correspondence: E-mail: sathonma{at}med.hokudai.ac.jp
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References |
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Received: 29 May 2006
Accepted: 12 July 2006
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  N. Hayasaka, T. Yaita, T. Kuwaki, S. Honma, K.-i. Honma, T. Kudo, and S. Shibata Optimization of Dosing Schedule of Daily Inhalant Dexamethasone to Minimize Phase Shifting of Clock Gene Expression Rhythm in the Lungs of the Asthma Mouse Model Endocrinology, July 1, 2007; 148(7): 3316 - 3326. [Abstract] [Full Text] [PDF]
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