When does it start ticking? Ontogenetic development of the mammalian circadian system

A. Kalsbeek, M. Merrow, T. Roenneberg and R. G. Foster (Eds.) Progress in Brain Research, Vol. 199 ISSN: 0079-6123 Copyright Ó 2012 Elsevier B.V. All rights reserved.

CHAPTER 6

When does it start ticking? Ontogenetic development of the mammalian circadian system Elmar Christ{,*, Horst-Werner Korf{,{ and Charlotte von Gall{,{,1 {

Dr. Senckenbergische Anatomie II, Fachbereich Medizin, Goethe-Universität Frankfurt, Frankfurt am Main, Germany { Dr. Senckenbergisches Chronomedizinisches Institut, Goethe-Universität Frankfurt, Frankfurt am Main, Germany

Abstract: Circadian rhythms in physiology and behavior ensure that vital functions are temporally synchronized with cyclic environmental changes. In mammals, the circadian system is conducted by a central circadian rhythm generator that resides in the hypothalamic suprachiasmatic nucleus (SCN) and controls multiple subsidiary circadian oscillators in the periphery. The molecular clockwork in SCN and peripheral oscillators consists of autoregulatory transcriptional/translational feedback loops of clock genes. The adult circadian system is synchronized to the astrophysical day by light whereas the fetal and neonatal circadian system entrains to nonphotic rhythmic maternal signals. This chapter reviews maturation and entrainment of the central circadian rhythm generator in the SCN and of peripheral oscillators during ontogenetic development. Keywords: circadian clock; ontogenesis; development; suprachiasmatic nucleus; pars tuberalis; adrenal gland; peripheral clock.

The circadian system and its molecular clockwork Based on the rotation of the Earth around its axis, the light conditions change rhythmically with a period length of 24 h (day). During phylogeny, circadian systems have evolved in nearly all living organisms to anticipate these rhythmic changes in environmental light conditions (Dunlap, 1999; Dvornyk et al., 2003; Johnson and Golden, 1999) and to drive rhythms in physiology and

*Corresponding author. Tel.: þ49-069-6301-83156; Fax: þ49-069-6301-6017 E-mail: [email protected]

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Current address: Zentrum für Anatomie und Hirnforschung, Institut für Anatomie II, Universitätsklinikum Düsseldorf, Life Science Center, Düsseldorf, Germany http://dx.doi.org/10.1016/B978-0-444-59427-3.00006-X

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behavior. In mammals, the circadian system is organized in a hierarchy of multiple oscillators. The central circadian pacemaker is located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. The SCN integrates light information conveyed by the retinohypothalamic tract (RHT) and coordinates peripheral oscillators distributed throughout the body. In each SCN neuron, a molecular clockwork consisting of autoregulatory transcriptional/translational feedback loops of clock genes drives rhythmic cellular properties and rhythmic output signals with a circadian period length ( 24 h) (Okamura et al., 2002; Reppert and Weaver, 2002). The transcriptional activators in the core molecular clockwork, CLOCK/NPAS2 and BMAL1 are characterized by a basic helix–loop–helix DNA-binding domain and two Per-Arnt-Sim protein interaction domains that allow for the formation of heterodimers. These heterodimers activate gene expression through E-box (like) enhancer elements located in the promoter region of the clock genes Per1, Per2, Cry1, and Cry2 and of so-called clockcontrolled genes. The protein products of the Per and Cry genes form repressor complexes that comprise additional proteins such as casein kinase 1 e and d. After translocation into the nucleus, the repressor complex inhibits CLOCK/ NPAS2:BMAL1-mediated transcription and thus suppresses its own transcription. A new cycle starts after hyperphosphorylation, ubiquitination, and proteasomal degradation of the repressor complex. This core negative feedback loop is modulated by accessory feedback loops that involve the orphan nuclear receptors REV-ERBa and RORa. By binding to ROR enhancer elements REV-ERBa and RORa control expression of Bmal1. As CLOCK and BMAL1 are constitutively present and bound to the E-box element throughout the circadian cycle, the circadian rhythm in gene expression depends mainly on the presence of the repressor complex (von Gall et al., 2003). The molecular clockwork genetically determines the endogenous circadian period length that varies with the species, for example, in

Syrian hamster it is 22.5 h (Ralph and Menaker, 1988), in laboratory mouse strains 23.6 h (Schwartz and Zimmerman, 1990; von Gall et al., 1998), and in humans 25 h (Aschoff, 1965). Period and phase of the circadian oscillation is entrained to the external rhythm by so-called zeitgebers (see below). The molecular clockwork controls the rhythmic expression of clock-controlled genes such as arginine vasopressin (AVP) (Jin et al., 1999), an important rhythmic SCN output signal (see below). Importantly, molecular clocks are not restricted to the SCN, but are present in peripheral oscillators such as other brain regions and peripheral organs (Balsalobre, 2002; McNamara et al., 2001; Oishi et al., 1998; Sun et al., 1997; Yoo et al., 2004; Zylka et al., 1998). Robust sustained oscillation of clock gene expression in the SCN and in peripheral oscillators depends on intercellular coupling (Liu et al., 2007). Within the SCN paracrine signaling via neuropeptides such as vasoactive intestinal peptide, AVP, and gastrin-releasing peptide provides powerful interneuronal communication (Maywood et al., 2011).

Synchronization mechanisms within the adult circadian system In the adult circadian system, phase and period length of the SCN molecular clockwork is entrained to the environmental day/night cycle by light. This entrainment is essential for normal physiology because long-term internal temporal desynchronization causes sleep disorders and chronic illnesses, such as cardiovascular disease, metabolic syndrome, and cancer (Hastings et al., 2003). Light during early or late night is a strong stimulus for delaying or advancing the phase of the molecular clockwork, respectively (Reppert and Weaver, 2002). Light information is transmitted to the SCN by glutamate and the neuropeptide PACAP released from specialized retinal ganglion cells projecting into the SCN (Reppert and Weaver, 2002). The activation of glutamate

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receptors during night activates the transcription factor Ca2 þ/cAMP-responsive element-binding protein (Gau et al., 2002), which activates the expression of mPer1 and mPer2 in the SCN (Albrecht et al., 1997; Gau et al., 2002; Shearman et al., 1997). The photic induction of Per expression is crucial for the daily adjustment of the endogenous rhythm of the molecular clockwork because light during early night delays the rhythm by activating Per in its declining phase, whereas light during late night leads to a precocious increase in Per expression, resulting in a phase advance (Hastings et al., 2003). The SCN transmits its phase and period to peripheral oscillators via paracrine, neuronal, and neuroendocrine output pathways. Behavioral rhythms such as circadian locomotor activity depend on diffusible signals from the SCN such as transforming growth factor (Kramer et al., 2001), cardiotrophin-like cytokine (Kraves and Weitz, 2006), and prokineticin 2 (Cheng et al., 2002; LeSauter et al., 1996; Ralph et al., 1990; Silver et al., 1996). In contrast, the circadian control of neuroendocrine rhythms requires intact neuronal projections from the SCN (Kalsbeek et al., 2000; LeSauter et al., 1996; Perreau-Lenz et al., 2003). Vasopressinergic SCN neurons provide an important output pathway of the SCN: they project to the paraventricular nucleus (PVN) of the hypothalamus. The PVN is a prime center for the control of both the autonomic nervous system and the neuroendocrine system. The autonomic nervous system that controls body homoeostasis originates from the dorsal parvocellular portion of the PVN which contains presympathetic and preparasympathetic neurons (Kalsbeek et al., 2006; Vrang et al., 1995). The presympathetic neurons send their axons to the intermediolateral column of the upper thoracic spinal cord, where they contact sympathetic preganglionic neurons. Postganglionic nerve fibers originating from the superior cervical ganglia regulate the nocturnal secretion of melatonin via the rhythmic release of norepinephrine (reviewed by Klein et al., 1991). GABAergic neurons in the SCN are involved in the inhibition of melatonin

release by light as well as in the control of the circadian rhythm in melatonin synthesis (Kalsbeek et al., 2006). Melatonin is an important rhythmic endocrine signal within the circadian system and can adjust the phase of the SCN rhythm generator (reviewed by von Gall et al., 2002b). Melatonin influences insulin production (reviewed by Peschke, 2008), modulates pain (reviewed by Ambriz-Tututi et al., 2009), synchronizes slave oscillators such as the pars tuberalis (PT) of the anterior pituitary (Jilg et al., 2005; Messager et al., 2000; Unfried et al., 2009, 2010; von Gall et al., 2001, 2005), and is believed to play a role in maintaining sleep throughout the night (reviewed by Cajochen et al., 2003). In addition, the SCN controls sensitivity of peripheral glands to pituitary hormones (Buijs et al., 2003) and the circadian rhythm in plasma glucose levels (Kalsbeek et al., 2004) via the autonomic nervous system. Neurons in the medial parvocellular PVH synthesize corticotropin-releasing hormone (CRH) which is secreted into the portal vasculature of the hypophysis (Kalsbeek et al., 2004) and regulates the secretion of adrenal corticosteroids via the hypothalamo-pituitary-adrenal (HPA) gland axis (Buijs and Kalsbeek, 2001). Vasopressinergic SCN output signals inhibit CRH release from the PVN and thus control the diurnal glucocorticoid (GC) rhythm (Kalsbeek et al., 1992; Tousson and Meissl, 2004). In mice with a corrupted molecular clockwork, the regulation of the HPA axis is defective (Oster et al., 2006b). Light can affect GC release from the adrenal by influencing either the HPA or the SCNsympathetic nervous system (Ishida et al., 2005). Moreover, the molecular clockwork in the adrenal gland gates GC production in response to adrenocorticotropin (ACTH) and controls rhythmic expression of a variety of genes involved in corticosterone biosynthesis (Oster et al., 2006a, b). GC levels show a strong daily oscillation in both laboratory rodents and humans, and represent an important phase entrainment signal within the circadian system (Balsalobre et al., 2000). In addition to rhythmic cues from the SCN, external

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rhythmic cues such as food intake also provide a strong entrainment signal for peripheral oscillators (Bur et al., 2010; Damiola et al., 2000; Schibler et al., 2003; Shibata et al., 2010; Stephan, 2002; Yamazaki et al., 2009).

Development of the central endogenous rhythm generator A complex and dynamic process of development prepares the embryo for the living conditions which it will experience after birth. In mammals, the embryos and fetuses receive important maternal signals for maturation and synchronization of the fetal circadian system via the placental system. In the early postnatal period, the intense social interaction with the mother as well as hormones in the milk still provides rhythmic maternal signals for the developing circadian system. These maternal signals might directly drive neonatal oscillators until the light input pathway and the SCN endogenous rhythm generator have fully developed. The SCN is formed during the third wave of hypothalamic neuron generation and develops as a component of the periventricular cell group. In rats (mean gestation period: 22 days), SCN neurons start to develop and differentiate between embryonic days 14–17 (E14–E17) and the adult morphology of the SCN is reached within postnatal day 10 (P10). The ventrolateral subdivision of the SCN develops around E14–E16, prior to the dorsomedial subdivision which develops around E16–E17 (Moore, 1991; Moore and Leak, 2001; Weinert, 2005). Circadian rhythms in SCN activity in rodents can be detected already in utero. The fetal rat SCN shows circadian rhythms in metabolic activity monitored by a 2-deoxyglucose uptake (Reppert and Schwartz, 1984a,b), Avp mRNA expression (Ansari et al., 2009; Reppert and Uhl, 1987), and neuronal firing rate between E19 and E22 (Shibata and Moore, 1987; Weinert, 2005). In melatonin-proficient C3H mice (mean gestation

period: 20 days), a circadian rhythm in Avp mRNA expression is evident as early as E18 (Ansari et al., 2009). However, it is still a matter of debate whether Avp expression is rhythmic in the fetal SCN as heteronuclear Avp RNA, which is supposedly a more reliable marker of transcription rate than mRNA, is not rhythmic until P1 in rat SCN (Kovacikova et al., 2006). The expression of clock genes in the fetal SCN is first detected at E13.5 in hamsters (mean gestation period: 16 days), at E17 in mice, at E19 in rats, and at E142 in capuchin monkeys (gestation period: 180 days). Thus, the molecular clockwork in the SCN starts to develop at around 90% of gestation in these species. In hamster SCN, circadian rhythms in clock genes (Bmal1, Per1, and Cry1) occur for the first time around P0 and clear rhythms can be detected at P2 (Li and Davis, 2005). In rat SCN, a circadian rhythm in Per1 occurs already at E20, while circadian rhythms of Bmal1 and Per2 start at P1 and of Cry1 at P2 (Kovacikova et al., 2006; Sumova et al., 2004, 2006). In acute SCN slice preparations from genetically modified rats bearing a Per1 promoter-driven luciferase (luc) reporter gene, a circadian rhythm in Per1 expression was found to persist for at least 4 days in vitro (Ohta et al., 2008). Clock gene proteins PER1, PER2, and CRY1 are undetectable in rat SCN at E19 (Sumova et al., 2004). In the SCN of capuchin monkey, a circadian rhythm in Bmal1 and Per2 becomes apparent at E142 (TorresFarfan et al., 2006a). In mouse SCN, mPer1, and mPer2 mRNAs are detectable at E17 (Shearman et al., 1997), but only mPer1 mRNA levels show a significant circadian rhythm during this fetal stage (Shimomura et al., 2001). There is a small but significant circadian variation in mPER1 and mPER2 immunoreaction in the SCN of C3H mice at E18, coincident with a low-amplitude circadian rhythm in Avp mRNA levels (Ansari et al., 2009). However, the rhythm of mCRY2 and mCRY1 levels starts only after birth at P2 and P10, respectively (Ansari et al., 2009; Shearman et al., 1997; Shimomura et al., 2001). This suggests that immature molecular clockwork driving rhythmic mPer

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expression might already be present in individual fetal mouse SCN neurons. Taken together, these results show that the endogenous circadian rhythm generator in the SCN starts to develop during late fetal stages and matures gradually during the postnatal period. In rodents, a mature molecular clockwork clock is established around P10. Coincidently, synapse formation, which is sparse at the time of birth, increases dramatically between P4 and P10 (Moore and Bernstein, 1989). Thus, synapse formation and consequently, synchronization between SCN neurons accounts for robust and coherent circadian rhythmicity in the developing SCN neuronal network (Moore, 1991). Circadian rhythms in AANAT activity in the pineal gland can be observed from P10 (Reppert et al., 1984) accurately reflecting rhythmic output from the developing SCN (Deguchi, 1982). Interestingly, the postnatal maturation of the molecular clockwork seems to be independent of rhythmic maternal cues as robust rhythms in Per1 and Per2 expression can be observed in organotypic SCN slice cultures derived from newborn (P4–P7) genetically modified mice and rats bearing luc reporter genes after 1 week up to several months in vitro (Yamaguchi et al., 2001; Yamazaki et al., 2000). It is still not known whether circadian rhythms in fetal SCN activity are driven by fetal SCN molecular clockwork. Although few mouse SCN cells show circadian rhythms in mPER1 and mPER2 levels (Ansari et al., 2009), there is no evidence that this is sufficient for driving rhythmic Avp expression. Moreover, the rhythms in clock gene expression in the fetal SCN might not be self-sustained as in the adult endogenous circadian rhythm generator but rather driven by rhythmic maternal cues in a peripheral oscillator-like manner. Importantly, an intact maternal SCN is indispensible for the synchronization of the embryonic/fetal circadian system. In newborn Syrian hamsters, the synchrony in rest/activity within the litter is lost after SCN lesion of the mother between E7 and E14 (Davis and Gorski, 1988). In rats, a lesion of the maternal SCN at

E7 leads to the disruption of circadian rhythms in SCN metabolic activity at E21 and pineal AANAT activity at P10 within the litter (Reppert and Schwartz, 1986). Synchronization within the fetuses of SCN-lesioned dams can be restored by rhythmic feeding cues (Weaver and Reppert, 1989). Thus, during fetal development, the circadian system is primed to prevailing lighting conditions by the maternal circadian system via endocrine and/or metabolic substances crossing the placenta (Reppert et al., 1984). Rearing of pubs born to SCN-lesioned dams by intact dams partially restores circadian rhythms in pineal AANAT activity at P10 (Reppert and Schwartz, 1986). This suggests that rhythmic cues from the mother are necessary and sufficient for entrainment of the newborns. However, the nature of these rhythmic maternal cues is still enigmatic; they can be provided by the social maternal behavior and/or the milk. As far as chemical messengers are concerned, both dopamine and melatonin have been shown to entrain the fetal circadian rhythms in metabolic activity (Davis and Mannion, 1988; Weaver et al., 1995). The melatonin receptor 1 (MT1) is expressed in the fetal SCN of different species (Thomas et al., 2002; Torres-Farfan et al., 2006a; Weaver and Reppert, 1996) and melatonin can readily cross the placenta (McMillen et al., 1990; Yellon and Longo, 1988). In capuchin monkeys, suppression of maternal melatonin by constant light leads to low expression levels of Per2 and MT1 and increased expression levels of Bmal1 in the fetal SCN. The effects on clock gene expression levels by constant light condition could be reversed with melatonin injections (Torres-Farfan et al., 2006a) indicating that maternal melatonin is capable to influence clock gene expression in the fetal SCN. This assumption is further supported by the observation that in the SCN of melatonin-deficient C57BL mice, rhythmicity of clock gene expression becomes evident only several days later (at P5; Huang et al., 2010) than in the SCN of melatonin-proficient C3H mice (Ansari et al., 2009). The hypothesis that maternal melatonin drives rhythmic clock gene expression in

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the fetal mouse SCN needs to be corroborated by comparative studies with melatonin (receptor)proficient and -deficient mice. Another rhythmic maternal cue that entrains rodent fetuses is dopamine acting on D1 receptors in the SCN (Viswanathan et al., 1994) and this pathway may provide the daytime signal. In addition to melatonin and dopamine, maternal behavior such as locomotor activity, body temperature, and periodic food intake could entrain the fetal SCN molecular clockwork. In Per1-luc transgenic rats, maternal feeding has been shown to entrain the fetal SCN independent of both the maternal SCN and the light–dark cycle (Ohta et al., 2008). Environmental lighting has no direct effect on the phase of fetal SCN metabolic activity (Reppert and Schwartz, 1983) and this is consistent with the observations that the light input pathway into the SCN develops postnatally (Mateju et al., 2009; Munoz Llamosas et al., 2000; Sumova et al., 2003; Weaver and Reppert, 1995). In rats, light stimuli were shown to induce the immediate early gene c-fos in the SCN as early as P0 (Leard et al., 1994; Weaver and Reppert, 1995). Per1 and Per2 mRNA expression in the SCN can be induced by light at P1 and P3, respectively (Mateju et al., 2009). At variance, in hamster and mouse SCN, Fos/Fos-like immunoreaction is inducible by light at P4 (Kaufman and Menaker, 1994; Reppert et al., 1984). This species difference might be a consequence of developmental differences in the formation of the RHT. However, under natural conditions, newborn rodents experience environmental light only rarely as they are raised in dens. Feeding and social interaction with the mother might be the most important rhythmic signals for the newborns. Rodents feed their pups during the day while the mother takes food during the night (Ohta et al., 2003). Most likely, melatonin is absent in the milk during day (Illnerova et al., 1993) and thus provides a reliable rhythmic maternal signal for the newborns. After weaning, photic input becomes the most important rhythmic cue for entrainment of the circadian system in the juvenile animals.

Ontogenesis of peripheral circadian oscillators Peripheral oscillators have different capacities for autonomous rhythmic expression of clock genes in vitro (Yoo et al., 2004). Some peripheral oscillators such as the liver show robust rhythmicity over several weeks while others damp out rapidly in vitro demonstrating their dependency on periodic rhythmic input for sustained rhythmic clock gene expression. An excellent model for a strongly inputdependent oscillator is the PT of the anterior pituitary. The PT is part of the anterior pituitary developing from a distinct antero-ventral area of Rathke’s pouch (Stoeckel et al., 1979). The adult PT is a major target of the hormone melatonin, which conveys photoperiodic information to the endocrine system (Hazlerigg, 2001; Lincoln, 2002; Morgan et al., 1994; Roca et al., 1996). Melatonin by acting on PT cells affects prolactin secretion from the anterior pituitary (Lincoln, 2002; von Gall et al., 2002a) presumably via PT-derived paracrine factors (called tuberalins) that act anterogradely on lactotrophs in the pars distalis (Morgan and Williams, 1996; Yasuo and Korf, 2011; Yasuo et al., 2010a,b). In addition, melatonin controls PT-derived thyrotropin which acts retrogradely and activates Dio2 expression in the ependymal cell layer of the infundibular recess (Yasuo et al., 2007, 2009, 2010b), thereby regulating local thyroid hormone levels in the mediobasal hypothalamus. The adult PT shows a rhythmic expression of clock genes which strongly depends on melatonin signaling via the MT1 receptor. In pinealectomized animals or in mice with a targeted deletion of the MT1, no rhythms in clock genes/proteins can be detected in the adult PT (Jilg et al., 2005; Messager et al., 2001; von Gall et al., 2002a, 2005). Importantly, circadian rhythms in clock proteins are already present in the fetal (E18) PT of melatonin-proficient mice. These rhythms are in phase with and show the same amplitude as those in the maternal PT (Ansari et al., 2009). This suggests that the PT circadian oscillator is already fully established in the

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embryonic stage. As the PT circadian oscillator is driven by the rhythmic melatonin signal and fetal rodents are not capable to produce melatonin rhythmically (Deguchi, 1975; Kennaway et al., 1992; Nowak et al., 1990), the oscillations in clock proteins in the fetal PT are presumably driven by maternal melatonin. The cortex of the adult adrenal gland controls metabolic homeostasis and circadian rhythms in energy balance via the hormone corticosterone. This hormone also represents an important rhythmic cue for other peripheral oscillators like the liver (Balsalobre et al., 2000; Reddy et al., 2007). Rhythmic corticosteroid production in the adult adrenal cortex is driven by the SCN by influencing both the hypothalamus-pituitary-adrenal (HPA) neuroendocrine axis (Abe et al., 1979; Buijs and Kalsbeek, 2001; Buijs et al., 2003) and the sympathetic nervous system (Buijs et al., 2003; Ishida et al., 2005; Lemos et al., 2006; Ulrich-Lai et al., 2006). Melatonin inhibits the activation of cortisol secretion induced by ACTH (Torres-Farfan et al., 2003, 2004). The adult adrenal cortex possesses a molecular clockwork (Bittman et al., 2003; Fahrenkrug et al., 2008; Ishida et al., 2005; Lemos et al., 2006; Oster et al., 2006b; Torres-Farfan et al., 2006b; Valenzuela et al., 2008) which gates rhythmic cortisol secretion in response to ACTH (Oster et al., 2006b). Melatonin-proficient mouse strains show circadian rhythms in clock gene expression in the adrenal cortex in contrast to melatonin-deficient mouse strains (Torres-Farfan et al., 2006b) suggesting an important role of melatonin for driving the adrenal cortex peripheral oscillator. The fetal rat adrenal gland (E18) shows circadian rhythms in clock gene expression and in cortisol secretion which persist at least for 2 days in vitro (Torres-Farfan et al., 2011). Melatonin affects the phase of clock gene expression in cultured adrenal glands (Torres-Farfan et al., 2011), suggesting that maternal melatonin might trigger the molecular clockwork in this developing peripheral oscillator. However, in the adrenal gland of fetal capuchin monkeys, the circadian rhythm in clock gene expression is not

synchronized by maternal melatonin (TorresFarfan et al., 2006a), demonstrating species-specific differences in the control of fetal peripheral oscillators. The liver has a very strong capacity for autonomous rhythmic expression of clock genes in vitro (Yoo et al., 2004). In the adult liver, a large number of genes (Akhtar et al., 2002; Panda et al., 2002; Reddy et al., 2007) and proteins (Reddy et al., 2006) involved in plasma protein synthesis, glycogen metabolism, detoxification, and the core molecular clockwork show circadian fluctuations. About 60% of the circadian liver transcriptome is driven by GCs (Reddy et al., 2007). In the fetal rat liver (E20), detection of clock genes by in situ hybridization did not reveal any circadian rhythms except for a low amplitude in Cry1 (Sladek et al., 2007). This study has also shown that the molecular clockwork in the liver matures even more slowly during postnatal development than the fetal SCN oscillator and rhythmic expression of all clock genes has been achieved only at P30 (Sladek et al., 2007; Sumova et al., 2004). In contrast, the fetal liver of Per1-luc transgenic rats shows a circadian rhythm in Per1 expression for at least 2 days in vitro that, similarly to the fetal SCN and the adult liver, can be entrained by maternal feeding (Ohta et al., 2008). Thus, the fetal liver represents a damped circadian oscillator that gradually matures during postnatal life.

Summary In fetal rodents, the SCN, adrenal gland, and liver show a circadian rhythm of clock gene expression, which persists for at least 2 days in vitro, demonstrating the existence of circadian fetal oscillators. These can be entrained by maternal cues such as melatonin (impact on SCN and adrenal gland), dopamine (SCN), and maternal feeding (SCN and liver). It is still a matter of debate whether the fetal SCN and the fetal adrenal gland produce rhythmic output signals, such as vasopressin, and cortisol, respectively, which might

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Rhythmic signals (e.g., feeding)

Melatonin

Placenta

Fetus

Rhythmic signals?

Fetal peripheral oscillators (e.g., liver, adrenal, PT)

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Relative optical density

Number of cells/SCN

Fig. 1. Model depicting synchronization of fetal circadian oscillators by rhythmic maternal cues. The endogenous rhythm generator in the maternal SCN is synchronized by light and generates circadian rhythms in melatonin and other hormones, body temperature, and metabolites. Via the placenta these rhythmic maternal signals reach the fetus in which they synchronize the SCN, and selfsustained peripheral oscillators, such as the liver and the adrenal gland, and drive input-dependent peripheral oscillators, such as the pars tuberalis of the pituitary (PT). It is still a matter of debate whether vasopressin or other rhythmic signals generated by the fetal SCN are capable of driving/synchronizing fetal peripheral oscillators. Modified after Reppert and Weaver (2002) and Ansari et al. (2009).

900 600 300 0 00

06 12 18 Circadian time

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Adult

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P10 P2 E18

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06 12 18 Circadian time

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Fig. 2. Analysis of mPER1-immunoreaction (Ir) in SCN (left) and PT (right) during mouse ontogenetic development (mean  SEM of five animals per time point and ontogenetic stage. Data points at CT00/24 are double-plotted). Fetal SCN and PT show low- and high-amplitude circadian oscillation of mPER1-Ir, respectively. Modified after Ansari et al. (2009).

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provide intrinsic entrainment signals to other peripheral oscillators in the fetus (Fig. 1). Alternately, peripheral oscillators in the fetus may be exclusively entrained by maternal signals until birth/weaning. The core molecular clockwork in SCN and liver, which represent robust selfsustained oscillators in the adult, matures gradually during postnatal development. In vitro studies suggest that this maturation is independent of rhythmic maternal cues. In contrast, the core molecular clockwork in strictly input-dependent oscillators, such as the PT, appears to be driven by maternal cues and matures already during fetal life (Fig. 2). In conclusion, maternal cues contribute to the ontogenetic development of circadian oscillators; depending on the organ, the signals from the mother can either drive or entrain the fetal and newborn clockwork.

Abbreviations ACTH AVP CRH E GC HPA luc MT1 NRC P PT PVN RHT SCN

adrenocorticotropin arginine vasopressin corticotrophin-releasing hormone embryonic day glucocorticoid hypothalamo-pituitary-adrenal luciferase melatonin receptor 1 negative regulator complex postnatal day pars tuberalis paraventricular nucleus retinohypothalamic tract suprachiasmatic nucleus

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