Postnatal ontogenesis of molecular clock in mouse striatum

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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s

Research Report

Postnatal ontogenesis of molecular clock in mouse striatum Yanning Cai a , Shu Liu a , Ning Li b,c , Shengli Xu a , Yanli Zhang a , Piu Chan a,⁎ a

Department of Neurology and Neurobiology, Xuanwu Hospital of Capital Medical University, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, 45 Changchun Street, Beijing 100053, PR China b Cell Therapy Center, Xuanwu Hospital of Capital Medical University, Key Laboratory for Neurodegenerative Diseases of Ministry of the Education, 45 Changchun Street, Beijing 100053, PR China c Laboratory of Cell and Development, College of Life Sciences, Capital Normal University, Beijing 100037, PR China

A R T I C LE I N FO

AB S T R A C T

Article history:

Striatum is an important brain area whose function is related to motor, emotion and

Accepted 6 January 2009

motivation. Interestingly, biological and physiological circadian rhythms have been found

Available online 10 January 2009

in the striatum extensively, suggesting molecular clock machinery works efficiently therein. However, the striatal expression profiles of clock genes have not been characterized

Keywords:

systematically. In addition, little is known about when the expression rhythms start during

Circadian

postnatal ontogenesis. In the present study, 24 h mRNA oscillations of 6 principle clock

Gene expression

genes (Bmal1, Clock, Npas2, Cry1, Per1 and Rev-erb α) were examined in mouse striatum, at

Postnatal

early postnatal stage (postnatal day 3), pre-weaning stage (postnatal day 14) and in adult

Striatum

(postnatal day 60). At P3, no daily oscillation was found for all clock genes. At P14, a significant time effect was identified only for Rev-erb α and Npas2. At P60, the daily oscillations of these clock genes were at least borderline significant, with peak time at Circadian time (CT) 01 for Bmal1, Clock, Npas2 and Cry1; at CT 13 for Per1; and at CT 07 for Rev-erb α. In addition, the overall mean mRNA levels of these clock genes also underwent a dynamic change postnatally. For Bmal1, Clock, Npas2, Per1 and Rev-erb α, the expression level increased throughout the postnatal ontogenesis from P3, P14 to P60. For Cry1, however, the abundance at P3 and P60 were similar while that at P14 was much lower. In conclusion, the striatal molecular clock machinery, although works efficiently in adult, develops gradually after birth in mice. © 2009 Published by Elsevier B.V.

1.

Introduction

In mammals, the hypothalamic suprachiasmatic nucleus (SCN) is the central pacemaker for physiological, metabolic and behavioral circadian rhythms. Many features of the intracellular molecular machinery of the SCN have been elucidated in the last decade (Reppert and Weaver, 2001). Briefly, the interlocking autoregulatory transcriptional and translational feedback loops consisting of positive and negative elements drive self-sustaining cellular clock oscillations. ⁎ Corresponding author. Fax: +86 1083161294. E-mail address: [email protected] (P. Chan). 0006-8993/$ – see front matter © 2009 Published by Elsevier B.V. doi:10.1016/j.brainres.2009.01.003

The positive components of the core feedback loop are a set of transcription factors, CLOCK:BMAL1 and/or NPAS2:BMAL1 heterodimers, which drive the rhythmic expression of three Period genes (Per1, Per2, and Per3) and two Cryptochrome genes (Cry1, Cry2). The resultant PER:CRY protein dimers act as negative components by translocating back into the nucleus and inhibiting CLOCK:BMAL1 and/or NPAS2:BMAL1 activities, thereby completing the negative limb of the feedback loop. In addition, the Rev-erb α protein acts to inhibit Bmal1 transcription and therefore forms an additional nega-

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tive loop to the cycle. A positive loop works through PER:CRY inhibition of Rev-erb α transcription; this inhibition of Rev-erb α lifts the Rev-erb α inhibition of Bmal1 transcription, thus activating the system. All of these positive and negative elements are identified as clock genes, and largely display a rhythmic expression. Posttranslational processes and some other secondary feedback loops also contribute to the precision of the core clockwork machinery (Dardente and Cermakian, 2007; Ko and Takahashi, 2006). In addition to the SCN, a number of areas of the mammalian brain and peripheral tissues also express circadian rhythms in clock gene expression, hormone output and electrical activity and are regarded as peripheral circadian oscillators which can be synchronized by the central oscillator (SCN) (Guilding and Piggins, 2007). Even though there are similarities between molecular clock machinery in the central and peripheral oscillators (Balsalobre et al., 2000; Nagoshi et al., 2004), brain clock rhythms are different than the rhythms in the SCN (von Gall et al., 2002). In addition, brain clocks also work as transcription factors in tissue specific fashion different than their functioning in the SCN, the expression of these transcription factors in the mammalian brain is not only intrinsically rhythmic but is also modulated by external inputs and hormones (Manev and Uz, 2006). Striatum is an important brain area whose function is related to motor, emotion and motivation. Interestingly, circadian rhythms have been found in the striatum for 1) extracellular concentrations of neurotransmitters and their main metabolites (Castañeda et al., 2004); 2) the expression of neurotransmitter related genes (Weber et al., 2004); 3) nitric oxide production (Itokawa et al., 2006); and 4) synaptic plasticity (Horowski et al., 2004), suggesting molecular clock machinery works efficiently in the striatum. Indeed, some clock genes, such as Per1 and Per2 have shown a rhythmic expression patterns therein (Uz et al., 2003; Masubuchi et al., 2007). However, the 24 h expression profiles of principle clock genes have not been characterized systematically. In addition, little is known about when the expression rhythms start in the striatum. To address the aforesaid issues, daily profiles of six principle clock gene expression (Bmal1, Clock, Npas2, Cry1, Per1 and Rev-erb α) were examined in mouse striatum during development, at early postnatal stage (postnatal day 3), pre-weaning stage (postnatal day 14) and in adult (postnatal day 60). Our results indicate that 1) molecular clock machinery works efficiently in adult striatum; 2) development of molecular clock in mouse striatum proceeds gradually after birth.

declined afterward then reached trough value at CT 13. At P60, the one-way ANOVA revealed a significant time effect for Bmal1, Clock, Npas2, Per1 and Rev-erb α with a p value less than 0.05 or a borderline significant daily oscillation for Cry1 with p = 0.063. Bmal1, Clock, Npas2 and Cry1 peaked at CT 01, the transition from dark to light span. However their trough times were a little bit different, at CT 13 to 19 for Bmal1, at CT 13 for Clock and Npas2, at CT 07 to 13 for Cry1. Per1 and Reverb α peaked at CT 13 and 07 respectively. The ratio between peak and trough value was 2.6 for Bmal1, 3.7 for Clock, 3.1 for Npas2, 1.8 for Cry1, 2.0 for Per1 and 2.7 for Rev-erb α.

2.2.

Developmental dynamics of Clock genes

The expression of clock genes can vary significantly throughout the day; thus, time-effects need to be taken into account when trying to compare distributions of these CGs during development. Thus, all individual samples collected aroundthe-clock were used to calculate the overall mean mRNA expression of each gene at each stage. For comparative purposes, the mean expression value of each gene in adult, P60, was arbitrarily set to 1, and the mean at other stages were expressed as a ratio relative to P60 (see Table 1). For Bmal1, Clock, Npas2, Per1 and Rev-erb α, the expression level was much less abundant at P3, and then increased to some extent at P14, and finally reached peak value in adult. For Cry1, however, the abundance at P3 and P60 were similar while that at P14 was much lower.

2.3. Balance between Bmal1:Clock and Bmal1:Npas2 during postnatal ontogenesis Bmal1:Clock and Bmal1:Npas2 can form heterodimers that activate the transcription of a variety of clock genes (CGs) and clock-controlled-genes (CCGs) (Dardente and Cermakian, 2007). The abundance of these transcription factors is postulated to be more or less comparable. To check this, the overall mean Bmal1/Clock and Bmal1/Npas2 ratios in adult were arbitrarily set to 1, and these ratios at early stages were expressed relative to adult. The expression levels of Bmal1 and Clock were indeed found to be comparable at both P3 (1.74) and P14 (1.16), although Bmal1 seemed to be more abundant at early postnatal days relative to Clock. Similarly, the expression levels of Bmal1 and Npas2 were also comparable at both P3 (1.75) and P14 (1.20), with Bmal1 seemingly more abundant at early postnatal days relative to Npas2.

2.4. Balance between positive and negative regulators during postnatal ontogenesis

2.

Results

2.1.

Rhythmic expressions of Clock genes

Twenty-four hour mRNA expression profiles of Bmal1, Clock, Npas2, Cry1, Per1 and Rev-erb α in the striatum of 3-, 14- and 60-day-old mice are shown in Fig. 1. At P3, the one-way ANOVA revealed no significant daily oscillation. At P14, a significant time effect was only present for Npas2 (p = 0.001) and Rev-erb α (p = 0.027). Npas2 mRNA levels peaked at CT 19. Rev-erb α mRNA levels peaked from CT 19 to 01 and then

The rhythmic expression of clock genes is a result of balancing between positive and negative regulators, with Bmal1, Clock and Npas2 belonging to the positive limb of the core clock feedback loop, and Per1, Cry1, and Rev-erb α belonging to the negative limb. To roughly compare the balance of positive and negative regulators during postnatal ontogenesis, the relative abundance of Bmal1 or Clock or Npas2 was divided by that of the negative regulators Per1, Cry1, and Rev-erb α in the same sample for each mouse to generate individual ratios and calculate an overall mean ratio. The nine mean ratios in adult

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Fig. 1 – 24 h mRNA expression profiles of clock genes Bmal1, Clock, Npas2, Cry1, Per1 and Rev-erb α in mouse striatum at postnatal 2-, 14-, 60 days. Animals were transferred into constant darkness at the time of the usual light onset and sacrificed at 6 h intervals beginning at 09:00 h local time (=CT 01), and the mRNA levels of each gene were assessed by real time RT PCR. Time is expressed as Circadian Time (CT), with CT 00-12 designating the subjective day. Real time PCR assay units expressed as % mean for comparison. Each point represents the mean of 4 animals ± SE. Data at CT 01 is plotted twice.

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Table 1 – Ratio of mean value of clock genes in mouse adult striatum versus developing striatum

Bmal1 Clock Npas2 Cry1 Per1 Rev-erb α

P3

P14

P60

0.43 0.28 0.30 0.95 0.55 0.29

0.54 0.49 0.50 0.54 0.70 0.69

1 1 1 1 1 1

were arbitrarily set to 1, while the ratios at other stages were expressed relative to adult (see Table 2). At P3, all of the nine ratios were below 1, which would indicate a balancing similar to in adult and suggest a balancing irregularity at early stage. At P14, ratios of Bmal1/Per1, Clock/Per1, Npas2/Per1, Bmal1/ Cry1, Clock/Cry1 and Npas2/Cry1 increased and got close to that in adult stage, on the other hand, ratios of Bmal1/Rev-erb α, Clock/Rev-erb α and Npas2/Rev-erb α decreased and were smaller than that in P3 and adult.

3.

Discussion

Lines of work have demonstrated biological and physiological circadian rhythms in the striatum which are believed to be regulated and sustained by local molecular clock machinery. Although the daily oscillations of clock genes (Per1, Per2) (Masubuchi et al., 2007) and clock controlled gene (DBP) (Yan et al., 2000) have been reported, the features of striatal molecular clock are largely elusive. In the present study, using real time RT PCR assay, we examined the expression profiles of 6 principle clock genes, (Bmal1, Clock, Npas2, Cry1, Per1 and Rev-erb α) in adult striatum. It indicated that 5 out of 6 clock genes fluctuated significantly around-the-clock. In addition, the daily oscillation of Cry1 was also borderline significant. This result suggests that molecular clock works efficiently in the mouse striatum. Regarding the time for their peak expression, the striatal molecular clock seems similar to other peripheral oscillators such as liver and kidney (Liu et al., 2007), with peak expression at late dark span or early light span for Bmal1, Clock, Npas2 and Cry1; at mid-light span for Rev-erb α and transition from light to dark for Per1. However, in the striatum the amplitudes of these clock genes were only around 2 to 4 folds, seems trivial compared with that in liver and kidney where 10 folds plus inductions were observed (Liu et al., 2007). Knowing that amplitudes of Per1 and Per2 in the cortex (Abe et al., 2004; Shimomura et al., 2001) were also less than 4, it seems to suggest that clock oscillations in brain areas outside SCN are indeed less robust than other oscillators in periphery. Although the molecular clock works efficiently in the adult striatum, it does not operate at early postnatal days or only works partially at pre-weaning stage. This result suggests that the postnatal development of molecular clock in mouse striatum proceeds gradually. Indeed, a gradual development of molecular clock machinery has been found in rodent SCN, cortex, liver and heart (Sakamoto et al., 2002; Shimomura et al., 2001; Sládek et al., 2004, 2007). Collectively, SCN is the

first site having mature clock machinery. No later than P2, rat SCN clock already operates with oscillations of most clock genes, which is much earlier than rat liver at P20 and rat heart at P14. While for mice, SCN operates at least partially at postnatal day 3 and efficiently at postnatal day 6, in great contrast with the late onset of striatal and cortical clock operation. Since even mouse embryonic fibroblasts that harbor peripheral circadian clock, can be synchronized in vitro (Panda et al., 2002), the late onset of the rhythms in clock gene expression in the striatum and the cortex might not be the result of intracellular immature clock machinery, rather it might reflect lack of synchronization from developing SCN which is indispensable in entraining functional individual oscillators in each brain area outside SCN. At the early postnatal days, the expressions of clock genes are constant. Knowing that most of these clock genes are transcription regulators, either transcription factors or repressors, it is reasonable to speculate that the constantly expressed clock genes may still regulate the transcription of a spectrum of downstream genes, such as CCGs and the number of genes important for the functioning of mesocorticolimbic system (McClung et al., 2005; Manev and Uz, 2006). Nevertheless, arrhythmic regulators are not likely to induce daily oscillations of downstream targets, and thus clock genes may function differently at early postnatal days than in adult. It is of interest to note that only Rev-erb α and Npas2 start rhythmic expressions at P14, while most of other clock genes are still arrhythmic. This result is in agreement with a recent report showing daily oscillation of Rev-erb α in fetal liver where all of the other clock genes were arrhythmic (Sládek et al., 2007). In addition, it was also reported that Rev-erb α is more sensitive to SCN signals and may serve as an initial molecular target (Li et al., 2008). Then an open question is straightforward, what's the mechanism underlying the fluctuations of Rev-erb α and Npas2 when positive and negative feedback loops are not ready to work, and warrants further study. Growing evidences suggested the existence of an SCNindependent methamphetamine-sensitive circadian oscillator (MASCO) in rodent (Ruis et al., 1990), which posses a key property of master circadian oscillator, i.e. driving circadian rhythms in locomotor activity, core body temperature and plasma corticosterone (Honma et al., 1986, 1987); free-running for up to 2 weeks after the cessation of methamphetamine treatment (Tataroglu et al., 2006). At present it is still unclear where the MASCO resides or how it exerts its actions,

Table 2 – Mean ratios of positive and negative regulators in mouse striatum during postnatal ontogenesis

Bmal1/Per1 Clock/Per1 Npas2/Per1 Bmal1/Cry1 Clock/Cry1 Npas2/Cry1 Bmal1/Rev-erb α Clock/Rev-erb α Npas2/Rev-erb α

P3

P14

P60

0.86 0.60 0.55 0.51 0.34 0.34 0.88 0.69 0.71

0.91 0.85 0.78 1.06 0.99 0.98 0.45 0.46 0.50

1 1 1 1 1 1 1 1 1

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however, some recent studies showed that chronic methamphetamine changed the rhythmic expression of Per1, Per2 and Bmal1 in caudate-putamen (IIjima et al., 2002), suggesting striatum may play a role in the generation of MASCO. In addition, the methamphetamine effects are stage dependent at least in rat (Vorhees et al., 1994), thus it would be of interest to examine whether the molecular clock can be synchronized and phase-shifted in developing striatum just as in the adult, which may help to address the role of striatum in generating methamphetamine dependent oscillations. In conclusion, our data demonstrate that striatal molecular clock although works efficiently in adult, develops gradually after birth in mice. These findings may shed lights on the understanding of molecular, biological and physiological circadian rhythms in the striatum.

4.

Experimental procedures

4.1.

Animals and tissue preparation

Male C57BL/6 mice were housed on a 12L:12D light–dark cycle (lights-on at 08: 00 h; lights-off at 20: 00 h), with food and water available ad libitum. Day of delivery was designated the postnatal day 0 (P0). For postnatal studies at P3 and P14, newborn pups were kept with their mother through the experiment. For study at P60, adult C57BL/6 mice were housed individually. Animals were transferred into constant darkness at the time of the usual light onset (=CT 00) and sacrificed at 6 h intervals beginning at 09:00 h local time (=CT 01). For each group, four animals were killed/ time point by rapid decapitation, and brains were removed from the skulls under dim red light. And the striatums were isolated by gross dissection, and immediately frozen in dry ice. Care of the mice was in accordance with the Institutional Animal Care and Use Committee guidelines at the Capital Medical University.

4.2.

RNA preparations and quantitative real-time RT-PCR

Total RNA was extracted from striatum using RNAeasy kit (Qiagen, CA, USA) according to the users manual, and then treated with RQ1 RNase free DNase I (Promega, CA, USA) to eliminate Genomic DNA contamination. To quantify the abundance of clock genes, total RNA (∼1 μg) was first reverse transcribed using Superscript II (Invitrogen, CA, USA) and random hexamers, and then cDNA equivalent of 50 ng of total RNA was amplified in an Opticon II system (MJ research, MA, USA) using SYBR-Green I real-time PCR kit (Takara, Japan). Each sample was analyzed in duplicate to ensure the accuracy of the data. 18S, a housekeeping gene, was used to normalize the differences in sample RNA content. Primer sequences for PCR amplification have been described previously (Liu et al., 2007).

4.3.

Statistical analysis

Daily profiles of clock genes are expressed as means of four animals± SE/time point. Data were analyzed by one-way ANOVA for time differences, with p b 0.05 was considered significant.

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Acknowledgments We thank Jingyan Song for helpful discussion. Research support for YC, SL, NL, SX, YZ and PC was provided by the National Natural Science Foundation of China (30400148, 30430280); The National 973 Project Grant of China (2006CB500701, 2006CB943703, 2007CB947704); The National 863 Project Grant of China (2006AA02A408, 2006AA02A112, 2006AA02A114); Scientific Project of Beijing Municipal Science & Technology Commission (D07050701350703, D07050701350706). REFERENCES

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