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Clock Gene Expression in the Submandibular Glands
M. Furukawa1,2,
T. Kawamoto1,
M. Noshiro1,
K.K. Honda1,
M. Sakai1,
K. Fujimoto1,
S. Honma3,
K. Honma3,
T. Hamada2 and
Y. Kato1,*
1 Department of Dental and Medical Biochemistry, and
2 Department of Prosthetic Dentistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8553, Japan; and
3 Department of Physiology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan;
Correspondence: * corresponding author, ykato{at}hiroshima-u.ac.jp
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ABSTRACT
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Clock genes, which mediate molecular circadian rhythms, are expressed in a circadian fashion in the suprachiasmatic nucleus and in various peripheral tissues. To establish a molecular basis for circadian regulation in the salivary glands, we examined expression profiles of clock-related genes and salivary gland-characteristic genes. Clock-related genes—including Per1, Per2, Cry1, Bmal1, Dec1, Dec2, Dbp, and Reverb —showed robust circadian expression rhythms in the submandibular glands in 12:12-hour light-dark conditions. In addition, a robust circadian rhythm was observed in amylase 1 mRNA levels, whereas the expression of other salivary-gland-characteristic genes examined was not rhythmic. The Clock mutation resulted in increased or decreased mRNA levels of Per2, Bmal1, Dec1, Dec2, and Dbp, and in Cry1–/– background, Cry2 disruption also increased or decreased mRNA levels of these clock-related genes and the amylase 1 gene. These findings indicate that the Clock- and Cry-dependent molecular clock system is active in the salivary glands.
Key Words: circadian rhythm • salivary gland • clock • amylase • Dec
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INTRODUCTION
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The rhythmic nature of mammalian behavior and homeostasis is regulated by a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus (Dunlap, 1999). The molecular core of the clock system is a transcription-translation feedback loop comprised of clock genes such as Clock, Bmal1, Per, and Cry, and their protein products. These endogenously generated rhythms are usually entrained to the light-dark cycle or other environmental conditions, with light itself and feeding times being the most significant cues that determine the daily rhythms.
A mutation in the Clock gene, the first clock gene identified in a vertebrate, causes abnormally arrhythmic behavior in constant dark (DD) conditions (Vitaterna et al., 1994; King et al., 1997). In Clock mutant mice, expression of clock and clock-controlled genes is disrupted, with reduced peak expression even in 12:12-hour light-dark (LD) conditions (Jin et al., 1999; Minami et al., 2002). In contrast, double disruptions of Cry1 and Cry2—but not Cry1 disruption alone—resulted in an immediate loss of circadian rhythmicity in behavior (van der Horst et al., 1999; Vitaterna et al., 1999) and constantly high Per1 expression in the SCN, retina, and liver through 24 hrs (Okamura et al., 1999). We recently reported that the basic helix-loop-helix transcription factors Dec1 and Dec2 were expressed in a circadian fashion in the SCN (Honma et al., 2002; Butler et al., 2004): Their promoter activities were up-regulated by Clock/Bmal1 heterodimers, and down-regulated by Per/Cry and Dec (Hamaguchi et al., 2004; Kawamoto et al., 2004; Sato et al., 2004). In addition, another clock-related gene, Reverb, is involved in circadian expression of Bmal1, and Dbp is a clock-controlled gene.
Previous studies have shown that most clock genes, such as Per, Cry, and Bmal1, are expressed in a circadian manner not only in the SCN but also in several peripheral tissues (Balsalobre et al., 1998; Zylka et al., 1998b). Furthermore, circadian gene expression rhythms continue in tissue explants kept in constant conditions, indicating the presence of a peripheral clock in each tissue. These findings raised the possibility that the molecular clock system may also be active in salivary glands. The circadian rhythms in salivary glands seem to play important roles in animal lives, controlling the intake of nutrition and the defense system, since robust circadian rhythms are observed in saliva secretion and levels of various hormones, growth factors, and immunoglobulins—including melatonin and cortisol—in saliva (Ferguson and Fort, 1974; Roth et al., 1974; Vakkuri, 1985). The facial autonomic nerve adjusts the secretion of saliva from the submandibular glands, and - and β-adrenergic receptor levels have circadian rhythms in the submandibular glands (Basso and Piantanelli, 2002). In addition, the enzymatic activity of -amylase in rat parotid glands has a circadian rhythm (Bellavia et al., 1992). Both nerve growth factor and epidermal growth factor (EGF) were originally isolated from murine submandibular glands (Cohen, 1962), and the concentration of EGF in the submandibular glands shows circadian rhythmicity (Siminoski et al., 1993). Furthermore, mucin 10 (Muc10) and cystatin C (Cst3) genes are expressed at high levels in the salivary glands (Tavera et al., 1990; Denny et al., 1996). However, no information on circadian rhythms of clock genes or salivary-gland-characteristic genes, including the -amylase gene (Amy1), has been reported. In the present study, we wanted to determine the expression profiles of these genes in mouse submandibular glands, and to learn whether mutations of Clock or Cry gene affect the gene expression.
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MATERIALS & METHODS
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Animals
Six-week-old male C57/BL6 mice (Crea Japan, Tokyo, Japan) were housed under 12:12-hour LD conditions for 19 days, and were killed at the indicated zeitgeber (ZT—an environmental agent or event that provides the stimulus setting or resetting a biological clock of an organism) time on day 20. In some studies, foods were withheld from ZT0 on day 19. A breeding colony of Clock mutant mice with a BALB/c background had been developed from mice originally supplied by Dr. J.S. Takahashi (Northwestern University, Chicago, IL, USA). Both male Clock/Clock mice and wild-type mice were housed in a 12:12 LD cycle. Cry1–/– and Cry1–/–Cry2–/– male mice (C57BL6: Ola 129 hybrid, from 8 to 12 mos old) were individually housed in a 12:12-hour LD cycle. All procedures were performed in compliance with standard principles and guidelines for the care and use of laboratory animals, Hiroshima University Graduate School of Biomedical Sciences and Hokkaido University Graduate School of Medicine.
RNA Extraction and Real-time Quantitative RT-PCR
Total RNA was extracted from mouse submandibular glands with the use of TRIzol reagent (Invitrogen, Carlsbad, CA, USA). Levels of mRNA were determined by real-time quantitative RT-PCR analysis with the ABI Prism 7900 sequence detection system (Applied Biosystems, Foster City, CA, USA). The sequences of TaqMan probes and primers were: 5'-FAM-TTCTATCTCATCCC ACCATCGGCCAC-TAMRA-3', 5'-ATCAGCCTCCTTTTT GCCTTC-3', and 5'-AGCATTTCTCCAGCATAGGCAG-3' for Dec1; 5'-FAM-AGATCAACTGCCTGGACAGCATCCTCAG-TAMRA-3', 5'-AAACCTCTGGCTGTTCCTACCA-3', and 5'-GGAATGTTGCAGCTCTCCAAAT-3' for Per1; 5'-FAM-ATCAGCTGCCTGGACAGTGTCATCAGGTAC-TAMRA-3', 5'-CCAGAGGAACTAGCCTATAAGAACCA-3', and 5'-GAACTCGCACTTCCTTTTCAGG-3' for Per2; 5'FAM-TGGAAGTCATCGTGCGCATTTCACA-TAMRA-3', 5'-CGAGATGCAGCTATCAAGAAGC-3', and 5'-TGTCCGCCA TTGAGTTCTATGA-3' for Cry1; 5'-FAM-TATGGACACAGAC AAAGATGACCCTCATGG-TAMRA-3', 5'-CAGTGCCACT GACTACCAAGAAA-3', and 5'-CCTCCCTTGCATTCTT GATCC-3' for Bmal1; 5'-FAM-TGAAGAAGGCAAGGAAAGT CCAGGTGC-TAMRA-3', 5'-AGGAACTGAAGCCTCAA CCAATC-3', and 5'-CTCCGGCTCCAGTACTTCTCAT-3' for Dbp; and 5'-FAM-TTTGAGGTGCTGATGGTGCGCTTTG-TAMRA-3', 5'-CTTCCGTGACCTTTCTCAGCA-3', and 5'-TGTGCGGCTCAGGAACATCAC-3' for Rev-erb. Sequences of TaqMan probe and primers for Dec2 have been previously described (Noshiro et al., 2004). TaqMan probes and primers for Amy1, Muc10, Cst3, Egf, and 18S RNA were obtained from Applied Biosystems. The values for mRNA levels, relative to internal control 18S RNA, are shown as the mean ± SEM for 3 mice.
Statistical Analysis
Significance of differences between two groups at ZT6 or ZT18 was analyzed by Student’s t test. Circadian rhythms during a 24-hour period were statistically analyzed by one-way analysis of variance (ANOVA).
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RESULTS
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Rhythmic Expression of Clock Genes and Amylase 1 Gene (Amy1) in the Submandibular Glands
Expression profiles of various clock-related genes in the submandibular glands in C57/BL6 mice were examined under light-dark (LD) conditions. Levels of Per1 mRNA were high at ZT6-ZT14 and relatively low at ZT18-ZT2, with the Per1 mRNA level at ZT14 four times higher than that at ZT2 (Fig. 1A ). Expression of Per2 and Cry1 mRNAs showed robust rhythms with large amplitudes (about 25-fold): Their peak time of expression was ZT14 (Figs. 1B, 1C). In addition, Cry1 mRNA expression had a lower peak at ZT22.
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Figure 1. Circadian profiles of clock-related genes in the submandibular glands. Six-week-old male C57/BL6 mice were housed under 12:12-hour LD conditions for 19 days, and were killed at the indicated zeitgeber time (ZT: lights on at ZT0, lights off at ZT12)) on day 20. Total RNA was isolated from the submandibular glands and subjected to real-time RT-PCR analysis. Per1, Per2, Cry1, Bmal1, Dec1, Dec2, Dbp, and Reverb mRNA levels (mean ± SEM, n = 3) were determined. P-values were calculated by one-way ANOVA analysis. Expression profiles of Per1, Per2, Cry1, Bmal1, Dec1, Dec2, Dbp, and Reverb were rhythmic. To examine the effect of starvation on Cry1 expression, we withheld foods for 26–46 hrs from ZT0 on day 19 (a dotted line).
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Bmal1 expression showed a reversed profile as compared with that of Per2: The mRNA expression reached a peak at ZT22, and decreased to extremely low levels at ZT6-ZT18, and the amplitude of peak and trough was 35-fold (Fig. 1D ). Dec1 and Dec2 showed rhythmic expression, with levels reaching a maximum at ZT14 and ZT10, respectively (Figs. 1E, 1F). Expression of Dbp and Reverb also showed robust circadian rhythms, with peak expression time at ZT10, and high amplitude of 35- and 50-fold, respectively (Figs. 1G, 1H). Rhythmicity of the expression of Per1, Per2, Cry1, Bmal1, Dec1, Dec2, Dbp, and Reverb in the submandibular glands was statistically significant for all cases (one-way ANOVA, p < 0.05).
In addition, we examined daily changes in mRNA levels of several salivary-gland-characteristic genes. Expression of Amy1 showed robust rhythmicity, with a peak at ZT14, and amplitude of peak and trough about 100-fold (Fig. 2A). The Amy1 expression also showed a lower peak at ZT22. In contrast, expression levels of salivary-gland-characteristic genes Muc10, Cst3, and Egf were not rhythmic (Figs. 2B–2D). Since salivary secretion is stimulated by eating, we examined the changes in Amy1 gene expression while withholding feeding. Fasting for 26–46 hrs before death shifted the main peak of Amy1 mRNA expression from ZT14 to ZT18 and abolished the lower peak at ZT22, whereas the robust circadian rhythm in Amy1 expression was maintained in the starved mice (Fig. 2A). A similar phase shift and disappearance of the second peak were also observed in the circadian rhythm of Cry1 expression (Fig. 1C). However, fasting had little effect on expression levels of Muc10, Cst3, and Egf, and did not induce their circadian rhythms (Figs. 2B–2D). These findings suggest that the circadian rhythm of Amy1 expression is driven primarily by the intrinsic clock system, and that feeding activity modulates the circadian rhythm of Amy1 and Cry1 expression.
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Figure 2. Daily expression profiles of the salivary-gland-characteristic genes in the submandibular glands. After mice were housed under 12:12-hour LD conditions for 19 days, expression levels (mean ± SEM, n = 3) of mRNAs for amylase 1 (Amy1), mucin 10 (Muc10), cystatin C (Cst3), and epidermal growth factor (Egf) were determined in the presence or absence (dotted lines) of foods. Foods were withheld at ZT0 on day 19, and the mice were killed at the indicated zeitgeber time (ZT—recorded in hours) on day 20. P-values without or within parentheses (the starved group) are shown in the panel. Fasting altered the expression profile of Amy1 mRNA, but it did not induce circadian rhythms of other salivary-gland-characteristic genes.
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Expression of Clock-related Genes in Clock/Clock Mice
Clock gene expression in the submandibular glands of Clock/Clock BALB/c mice and wild-type mice was examined at ZT6 and ZT18. The Clock mutation affected the expression of all examined clock genes—including Per2, Bmal1, Dbp, Dec1, and Dec2—at ZT6 or ZT18 (Figs. 3A–3E). Expression levels of Amy1 in Clock/Clock mice showed a wide variation, and it was unclear whether Amy1 expression was affected by the Clock mutation (Fig. 3F).
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Figure 3. Expression of clock-related genes in the submandibular glands in Clock/Clock mice. Wild-type (WT) and Clock/Clock (Ck/Ck) mice were housed under LD conditions and killed at ZT6 or ZT18. Per2, Bmal1, Dbp, Dec1, Dec2, and Amy1 mRNA levels (mean ± SEM, n = 3) were determined. * P < 0.05 (standard t test).
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Expression of Clock-related Genes in Cry1–/– and Cry1–/–Cry2–/– Mice
Clock gene expression in the submandibular glands in male Cry1–/– and Cry1–/–Cry2–/– mice was examined: In the Cry1–/–mutant, Cry2 disruption increased expression of all examined clock genes—including Per2, Bmal1, Dbp, Dec1, and Dec2—at ZT6 (Figs. 4A–4E), and the disruption decreased Amy1 expression at ZT18 (Fig. 4F). Similar results were obtained with female Cry1–/– and Cry1–/– Cry2–/– mice (data not shown).
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Figure 4. Expression of clock-related genes in the submandibular glands in Cry1–/– and Cry1–/–Cry2–/– mice. Cry1–/– and Cry1–/–Cry2–/– mice were housed under LD conditions and killed at ZT6 or ZT18. Per2, Bmal1, Dbp, Dec1, Dec2, and Amy1 mRNA levels (mean ± SEM, n = 3) were determined. * P < 0.05 (standard t test).
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DISCUSSION
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In the present study, we showed that the clock and clock-related genes—Per1, Per2, Bmal1, Cry1, Dec1, Dec2, Dbp, and Reverb—in the submandibular glands have circadian expression rhythms: The phases and peaks of their expression were similar to those in the liver (Furukawa et al., unpublished observation), but different from those in the SCN (Zylka et al., 1998a; Butler et al., 2004). A recent report (Ueda et al., 2005) demonstrated that promoter regions of Per1, Per2, Dec1, Dec2, Dbp, and Reverb contain E/E' boxes (Clock/Bmal1-binding sites) and D boxes (Dbp-binding sites), which could be responsible for their circadian expression, with a peak at ZT10-ZT14. In contrast, the RevErbA/ROR element in the Bmal1 promoter could contribute to the circadian expression of Bmal1 mRNA, with a peak at ZT22-ZT2. These elements may also be involved in circadian regulation of clock genes in the salivary glands.
We found that the expression of Amy1 mRNA had a robust circadian rhythm, with peaks at ZT14 and ZT22. Since amylase accumulation is thought to decrease after mice start to eat at night, new synthesis of amylase is likely required at night, and the observed circadian rhythm of Amy1 expression is suitable for supplying large amounts of amylase at night. We also noted that both Amy1 and Cry1 expression profiles have two peaks at ZT14 and ZT22, and that in the 5'-flanking region (3 kb) and the first exon and intron of the Amy1 gene, there are five putative RevErbA/ROR elements, three putative D boxes, and an E box. The Cry1 gene also contains two RevErbA/ROR elements and an E/E' box, and the combined effects of these two types of promoter elements may produce the intermediate phase expected from transcriptional regulation involving E/E' boxes and RevErbA/ROR elements (Ueda et al., 2005). In the present study, we found that fasting shifted the first peaks of Amy1 and Cry1 expression profiles from ZT14 to ZT18 and abolished the second peaks at ZT22. These findings suggest that a similar transcriptional machinery contributes to Amy1 and Cry1 expression, and that the second peaks at ZT22 are produced by feeding behavior. The first peaks of Amy1 and Cry1 may be linked to circadian regulation through E/E' boxes and RevErbA/ROR elements. Since fasting resulted in single-peaked diurnal fluctuation in Cry1 and Amy1 expression, it is apparent that double-peaked oscillation was produced by the combination of feeding and circadian-dependent transcriptional regulation. Fasting isolated the effects of regulatory elements and, therefore, produced the oscillation with a single peak. The timing of peaks and troughs in Cry1 and Amy1 expression was different from that of Per1 and Bmal1, which suggests that the combinatorial regulation of the E/E' box and the RevErbA/ROR element might determine the distinct timing of peaks and troughs.
Previous studies showed that, in peripheral tissues of Clock/Clock mice, the expression of Per2 and Dbp decreased at almost all circadian times, whereas Bmal1 expression was constitutively high throughout the day (Oishi et al., 2000; Minami et al., 2002). In this study, the Clock mutation also decreased the expression of Per2, Dbp, and Dec2, and increased Bmal1 expression in the submandibular glands at ZT6. In the retina and liver of Cry1–/– mice, Cry2 disruption increased Per1 and Per2 expression at almost all circadian times (Okamura et al., 1999). Similarly, in Cry1–/–submandibular glands, the Cry2 disruption increased Per2, Bmal1, Dbp, Dec1, and Dec2 expression at ZT6. Thus, circadian rhythms of clock gene expression in the submandibular glands were also Clock- and Cry-dependent.
The Cry2 disruption markedly decreased Amy1 mRNA levels at ZT18, suggesting Cry-dependent regulation of the Amy1 gene. Arrhythmic behavior—including feeding activity—of Cry1–/–Cry2–/– mice could affect Amy1 expression indirectly. However, the rhythmic expression of Amy1 mRNA was maintained in the presence of the intrinsic clock system of wild-type mice, regardless of whether mice were fed or not, but forced fasting delayed the circadian phase of Amy1 expression. The intrinsic clock system may thus interact with external stimuli—including feeding cues—to maintain circadian rhythms in the salivary glands.
Since the mRNA level of Amy1 at ZT14 is about 100-fold higher than that at ZT18, the half-life of Amy1 mRNA was very short (Fig. 2A). The rapid degradation rate of Amy1 mRNA is comparable with those of Dbp and Reverb (Figs. 1G, 1H), and this may be accounted for by the presence of the AU-rich element (ARE)—WWWWAUUUAWWWW—in its 3'-UTR. We identified an ARE in the 3'-UTR of Amy1. ARE in the 3'-UTR is responsible for the instability and rapid turnover of mRNAs (Bakheet et al., 2003): From 5 to 8% of human genes—including Dbp and Reverb—carry ARE in the 3'-UTR. The rapid mRNA turnover is thus essential for circadian rhythms of gene expression.
Saliva contains numerous enzymes, hormones, growth factors, immunoglobulins, and other bioactive substances. The amount of saliva and secretion levels of these substances have circadian rhythms, which seem to be important for effective nutrition and self-defense. In the present experiment, we showed that circadian expression rhythms were detected in some salivary-gland-characteristic genes, but not in others-including Muc10, Cst3, and Egf. However, the amount of protein products of these genes may be controlled in a circadian fashion at secretion levels. In any case, the presence of a physiologically functional molecular clock system in the submandibular glands should be beneficial for swift ‘entrainment’ to the ‘master clock’, on the one hand, and to feeding cues on the other.
In conclusion, the circadian rhythms of mRNA expression of clock genes—including Per2, Cry1, Bmal1, Dbp, and Reverb—and of the Amy1 gene in the salivary glands were distinct. The peak-trough amplitudes were 20- to 50-fold—findings which indicate that the molecular clock system in the salivary glands is physiologically significant.
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ACKNOWLEDGMENTS
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This work was supported by grants-in-aid for science from the Ministry of Education, Culture, Sport, Science and Technology of Japan.
Received for publication January 11, 2005.
Revision received June 6, 2005.
Accepted for publication August 4, 2005.
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Journal of Dental Research, Vol. 84, No. 12,
1193-1197 (2005)
DOI: 10.1177/154405910508401219
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ABSTRACT
INTRODUCTION