Circadian clocks during embryonic and fetal development

Abstract

Circadian rhythmicity is a fundamental characteristic of organisms, which helps ensure that vital functions occur in an appropriate and precise temporal sequence and in accordance with cyclic environmental changes. Living beings are endowed with a system of biological clocks that measure time on a 24-hr basis, termed the circadian timing system. In mammals, the system is organized as a master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus, commanding peripheral clocks located in almost every tissue of the body. At the cell level, interlocking transcription/translation feedback loops of the genes Bmal-1, Clock, Per1-2, and Cry1-2, named clock genes, and their protein products results in circadian oscillation of clock genes and of genes involved in almost every cellular function. During gestation, the conceptus follows a complex and dynamic program by which it is simultaneously fit to develop and live in a circadian environment provided by its mother and to prepare for the very different environment that it will experience after birth. It has been known for a number of years that the mother tells the fetus the time of day and season of the year, and that the fetus uses this information to set the phase of fetal and neonatal circadian rhythms. There is evidence that the maternal rhythm of melatonin is one of the time signals to the fetus. In the last few years, the study of the development of the circadian system has turned to the investigation of the oscillatory expression of clock genes and their possible role in development, and to answering questions on the organization of the fetal circadian system. Emerging evidence shows that clock genes are expressed in the oocyte and during early and late development in embryo/fetal organs in the rat and in a fetal primate. The data available raise the intriguing possibility that the fetal SCN and fetal tissues may be peripheral clocks commanded by separate maternal signals. The rapid methodological and conceptual advances on chronobiology may help to unravel how the developing embryo and fetus faces time in this plastic period of life.

The Uterus Sustains Stable Biological Clock during Pregnancy

“…Previous studies have suggested that the fetus in the uterus uses maternal signals to adapt the fetal biological clock to the maternal environment (Reppert and Schwartz 1983;Davis and Gorski 1988;Parraguez et al 1996;Kennaway 2002;Ohta et al 2002Ohta et al , 2003Ohta et al , 2008Sládek et al 2004;Li and Davis 2005;Saxena et al 2007). These signals are considered to be a variety of nonphotic stimuli including circadian fluctuations in hormonal and nutritional signals from the mother, placental filtering of those signals, and uterine motility (Serón-Ferré et al 2007). The present study further supports this idea particularly by first proving the existence of stable circadian clocks in the pregnant uterus and the decidua at the molecular level.…”

“…Among them the suprachiasmatic nuclei (SCN) of the anterior hypothalamus function as the master pacemaker at the top of the hierarchy, and coordinate clocks in peripheral organs such as the heart, lung, liver, kidney, pancreas and non-pregnant uterus (Hastings et al 2003;Dolatshad et al 2006;Maywood et al 2007). During pregnancy, the fetus itself functions as an organ oscillator in the mother and uses maternal signals to adjust the fetal biological clock to the extrauterine environment (Serón-Ferré et al 2007;Ohta et al 2008).…”

“…In mammals, maternal melatonin has a circadian pattern in its plasma concentration and is thought to convey information on the light-dark cycle to the fetus, thereby synchronizing the developing fetus's biologic clock to the 24-hour cycle (Davis and Mannion 1988;Illnerová et al 1993;Serón-Ferré et al 2007). Fetal biological clock has also been reported to be influenced by the maternal feeding schedule during pregnancy (Weaver and Reppert 1986;Ohta et al 2008).…”

“…The intrauterine environment is suggested to be a circadian environment in which fetuses are subject to a variety of nonphotic stimuli, including circadian fluctuations in hormonal and nutritional signals from the mother, placental filtering of those signals, and uterine motility (Serón-Ferré et al 2007;Ohta et al 2008). In mammals, maternal melatonin has a circadian pattern in its plasma concentration and is thought to convey information on the light-dark cycle to the fetus, thereby synchronizing the developing fetus's biologic clock to the 24-hour cycle (Davis and Mannion 1988;Illnerová et al 1993;Serón-Ferré et al 2007).…”

The role of the neural sympathetic and parasympathetic systems in diurnal and sleep state-related cardiovascular rhythms in the late-gestation ovine fetus

“…Diurnal rhythms in fetal HR and HRV are well established in late gestation in the fetal human (44), nonhuman primates (39), and sheep (3,4,9,11,42). These circadian rhythms are thought to be entrained by maternal signals (28) and coordinated, in part, by signals from a fetal "biological clock" in the suprachiasmatic nucleus (SCN) (5,26,41), although other fetal tissues may be involved (37). A study in infants and children showed a circadian rhythm in HR and HRV and confirmed progressive maturation of the autonomic nervous system with age, suggesting the hypothesis that the sympathetic withdrawal associated with mature, organized sleep is largely responsible for those rhythms (24).…”