Chapter 5 - Circadian system from conception till adulthood
Introduction
The mammalian internal timekeeping system, which temporally controls many processes in our body, undergoes developmental changes as an organism grows and matures. Increasing awareness of the mechanisms of how the system operates at molecular level facilitates studies of the development of the system from its very early stages, that is, far before the overt rhythms driven by the system can be used as a marker of its functional stage. These studies may uncover the mystery of when the circadian clock begins to tick independent of the maternal environment. It is possible that the circadian clock is functional early prenatally when it resides in the maternal body and the mother's role is just to adjust its phase according to the external light/dark (LD) cycle to ensure that her offspring are born with fully entrained clocks. Alternatively, it is also possible that the developing circadian clock is first directly driven by maternal signals as a slave oscillator in utero and develops into a self-sustained clock that is sensitive to the external LD cycle only gradually after birth. Both possibilities would ensure that the newborn leaves the maternal body with its clock properly entrained with the external environment, but it remains unclear which of these possibilities would be evolutionally more advantageous. It is also possible that different species utilize various scenarios of the development. This issue is important for understanding the significance of mother-to-fetus and mother-to-neonate communication for proper development of the circadian system. Enormous amounts of data have been accumulated to demonstrate that a malfunction of the circadian system leads to the distortion of temporal control of physiology and results in the development of serious diseases. Studies on the ontogenesis of the circadian system may reveal whether its malfunction in adulthood may result from an insult during early developmental stages, which might arise from the disruption of the endogenous timekeeping system during pregnancy.
The circadian system is composed of hierarchically organized circadian clocks forming an integral regulatory system that gives the organism the daily temporal program and helps it adapt to the external environment. Circadian clocks reside in nearly every, if not all, mammalian cells (for a review, see Schibler et al., 2003). These clock cells are equipped with a set of so-called clock genes, which are genes that are indispensable for circadian function. In mammals, Per1, Per2, Cry1, Cry2, Bmal1, Clock, Rev-erbα, and Rora have been recognized as clock genes (for a review, see Takahashi et al., 2008). Cellular clocks are regularly entrained by the master pacemaker located in the suprachiasmatic nuclei (SCN) of the ventral hypothalamus just above the optic chiasm (Klein et al., 1991). The SCN is a complex structure, which is composed of a cluster of independent cellular oscillators (Welsh et al., 1995) that are mutually coupled by a web of synapses. This intercellular communication is responsible for synchrony among the cells (Liu et al., 2007). Moreover, the SCN cells are organized into morphologically and functionally distinct subpopulations (Klein et al., 1991) which also communicate among each other. The most prominent subpopulations are located in the ventrolateral (core) and dorsomedial (shell) regions of the SCN (for a review, see Welsh et al., 2010), but there are also other subdivisions, including a functional specialization in populations of cells in the rostro-caudal dimension of the SCN (Brown and Piggins, 2009, Morin, 2007, Sosniyenko et al., 2009). As a result of this intercellular communication, the SCN generates a synchronized output signal to the rest of the body that entrains the peripheral clocks with the external LD cycles.
This chapter provides a summary of our latest knowledge and offers some hypotheses on the processes by which the circadian system develops in mammals from its origin through weaning and adulthood. The summary includes mostly data from rodent models. For a more extensive overview of the subject, the readers are encouraged to refer to previous reviews (e.g., Weinert, 2005, Sumova et al., 2006a, Sumova et al., 2006b, Sumova et al., 2008, Seron-Ferre et al., 2007).
Section snippets
Prefetal development
The development of circadian clocks in mammals is intrinsically programmed and does not depend on presence of a functional maternal clock (Davis and Gorski, 1988, Jud and Albrecht, 2006, Reppert and Schwartz, 1986, Shibata and Moore, 1988). At the cellular level, the first appearance of circadian rhythmicity has been detected in differentiated, multipotent cells derived from embryonic stem cells but not at earlier stages such as pluripotent cells (Kowalska et al., 2010, Yagita et al., 2010).
SCN develops postnatally
With the postnatal progression of synaptogenesis in the SCN (Moore, 1991), the coupling among individual cellular oscillators is strengthened and reaches an adult-like state at P10. At the same time, the number of astrocytes in the SCN rapidly increases (Munekawa et al., 2000). Moreover, the intrinsically photosensitive retinal ganglion cells that mediate photic information from the retina begin to innervate the SCN only during this period (McNeill et al., 2011). Although this innervation
LD cycle entrains the developing clock in the SCN
As previously mentioned, the mechanism of photic entrainment of the SCN likely develops once the pups begin to move independently in the burrow and the probability of their light exposure increases. In rats, photic entrainment was indicated already at P6 (Duncan et al., 1986, Weaver and Reppert, 1995). The development of this mechanism is not completely understood. Morphologically, the neuronal projection from the retina to the SCN develops gradually during the postnatal period. At P1, the
Effect of disturbing the circadian system during early ontogenesis may persist through adulthood
From data summarized above, it appears that the circadian system is sensitive to disturbances in the external environment during early developmental stage; no matter whether they are related to changes in LD cycles or to the feeding regime. It is still unclear whether these changes may have long-lasting effects on the organism and whether they may persist till adulthood.
Some results indicate that light experience during the early postnatal period may affect clock function and clock output in
Conclusion
Studies focused on unraveling the basic principles of circadian clock development during early ontogenesis have uncovered an enormous plasticity of the whole system, which seems dependent on the development of its individual bricks of which it is built. These studies also point out the necessity of a detailed understanding of the processes by which the circadian system develops. This importance is underscored by the findings that intervention of the system by various cues during development may
Acknowledgments
The study was supported by grant nos. 305/09/0321, P303/11/0668, P303/12/1108, NT11474-4/2010, and LC554, and by Research Project AV0Z 50110509.
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