Clock genes in calendar cells as the basis of annual timekeeping in mammals--a unifying hypothesis

Abstract

Melatonin-based photoperiod time-measurement and circannual rhythm generation are long-term time-keeping systems used to regulate seasonal cycles in physiology and behaviour in a wide range of mammals including man. We summarise recent evidence that temporal, melatonincontrolled expression of clock genes in specific calendar cells may provide a molecular mechanism for long-term timing. The agranular secretory cells of the pars tuberalis (PT) of the pituitary gland provide a model cell-type because they express a high density of melatonin (mt1) receptors and are implicated in photoperiod/circannual regulation of prolactin secretion and the associated seasonal biological responses. Studies of seasonal breeding hamsters and sheep indicate that circadian clock gene expression in the PT is modulated by photoperiod via the melatonin signal. In the Syrian and Siberian hamster PT, the high amplitude Per1 rhythm associated with dawn is suppressed under short photoperiods, an effect that is mimicked by melatonin treatment. More extensive studies in sheep show that many clock genes (e.g. Bmal1, Clock, Per1, Per2, Cry1 and Cry2) are expressed in the PT, and their expression oscillates through the 24-h light/darkness cycle in a temporal sequence distinct from that in the hypothalamic suprachiasmatic nucleus (central circadian pacemaker). Activation of Per1 occurs in the early light phase (dawn), while activation of Cry1 occurs in the dark phase (dusk), thus photoperiod-induced changes in the relative phase of Per and Cry gene expression acting through PER/CRY protein/protein interaction provide a potential mechanism for decoding the melatonin signal and generating a long-term photoperiodic response. The current challenge is to identify other calendar cells in the central nervous system regulating long-term cycles in reproduction, body weight and other seasonal characteristics and to establish whether clock genes provide a conserved molecular mechanism for long-term timekeeping.

The regulation of neuroendocrine function: Timing is everything

“…Several hypotheses have been proposed to account for how the SCN and its targets track time on a seasonal basis Hofman, 2004;Lincoln et al, 2003). In the SCN of Syrian and Siberian hamsters, photoperiod alters the duration of clock and clock-controlled gene expression, while the amplitude of gene expression is influenced by photoperiod in the pars tuberalis Messager et al, 2000).…”

“…In the SCN of Syrian and Siberian hamsters, photoperiod alters the duration of clock and clock-controlled gene expression, while the amplitude of gene expression is influenced by photoperiod in the pars tuberalis Messager et al, 2000). In sheep, however, the relative timing of clock genes is altered by photoperiod in the pars tuberalis, providing a mechanism of temporal encoding and downstream control (Hazlerigg et al, 2004;Lincoln et al, 2002Lincoln et al, , 2003Lincoln et al, , 2005. These correlational results are intriguing and suggest that phase and/or amplitude of clock and CCGs in SCN brain targets and endocrine glands may predict their responsiveness to upstream signals on a daily schedule.…”

Neel revisited: the adipocyte, seasonality and type 2 diabetes

“…Melatonin affects hypothalamic clock gene expression and has systemic effects on other tissues in the body [32]. Within the hypothalamus, a complex system of positive and negative feedbacks occur on the clock genes that lead to the development of an oscillating system that essentially regulates the cyclical phenotype in response to day length and the seasons [32][33][34]. One remarkable finding has been the recognition that peripheral tissues have intrinsic clock activity (critically, including the adipocyte [35]), suggesting a hierarchy of regulatory mechanisms that keep the organism in time with its environment [33].…”

“…One remarkable finding has been the recognition that peripheral tissues have intrinsic clock activity (critically, including the adipocyte [35]), suggesting a hierarchy of regulatory mechanisms that keep the organism in time with its environment [33]. A second equally astonishing finding is that there appear to be two clock pathways, one involving the pineal gland, which regulates short photoperiodicity, and a second involving pituitary calendar cells, which has much longer term effects [34]. The latter process seems to be more embedded in longer living animals, and there is evidence that this cycle survives migration from the tropics to the northern hemisphere and even through subsequent generations [36].…”

“…In an elegant review on the mechanisms of seasonal rhythymicity in mammals, Lincoln et al [34] stated that 'humans express all elements of photoperiodism and circannual rhythm generation, albeit in a relatively weak fashion compared with many non-primate species'. This rhythmicity is reflected in man by changes in carbohydrate metabolism and weight gain, as well as behavioural and reproductive responses [34]. Substantial interest has developed in the general effects of disruption of this rhythmicity on health in man [40,41].…”