Thyrotrophin signalling at the core of photoperiodic time-measurement

Life on Earth has to cope with constantly changing environments. Some of this change is predictable, due to the daily light dark cycle, or to the annual cycle of seasonal change, and animals have evolved biological clocks to optimise their responses to rhythmic environments. These clocks are synchronised primarily through their responses to environmental lighting. In mammals, a key part of the seasonal timing process is the production of a hormone, called melatonin, by the pineal gland. Melatonin is only produced at night, in a temporal pattern that reflects the night-length, and changes in its pattern of production and secretion are known to be a key part of the process whereby animals time seasonal cycles of breeding, moulting and hibernation. Understanding of the genetic mechanisms elements underlying this physiology is of increasing importance since global changes in temperature are predicted to have profound disruptive effects on seasonal timing. This project focusses on the proposal that the mechanisms of melatonin action in mammals, actually depend on melatonin's effects on brain sensitivity to another hormone called thyroid hormone. Thyroid hormone is well known for its effects on animals' 'metabolic rate' - their rate of living, which is essentially the ultimate focus of seasonal changes such as entry into hibernation. So the concept that seasonal changes depend on modulation of the influence of thyroid hormone is intuitively attractive. The effects of melatonin in which we are interested are actually highly localised to the base of the brain, at the interface between the hypothalamus and the pituitary. This region of the brain is specifically concerned with metabolic control, and the timing of breeding. Here, we have identified a link between melatonin-sensitive cells in the pituitary and cells in the adjacent hypothalamus which control thyroid hormone levels in this area. This link is the local production of another hormone called thyroid stimulating hormone (TSH) by melatonin responsive cells, which acts on adjacent hypothalamic brain cells carrying specialised 'receptors' for TSH. The project wishes to explore the importance of this link, in terms of the ways in which melatonin controls TSH production, and the consequences of TSH acting on the adjacent hypothalmus. This project is of considerable interest because the mechanism we are exploring appears to have features in common with that in birds and amphibians, suggesting that it may be an ancient core mechanism. Additionally the novel concept of local actions of TSH by the route we describe has biomedical relevance since several metabolic disorders, including Grave's Disease, stem from abnormal TSH signalling.

In vertebrates, seasonal timing mechanisms involve changes in thyroid hormone related signalling in the hypothalamus. This is conserved in birds and mammals, even though the upstream photoperiodic readout mechanisms differ considerably. In mammals, which are the focus of this project, a key part of the biological timing process is the production of a hormone, melatonin, by the pineal gland. Melatonin is only produced at night, in a pattern that reflects the night-length, and it acts on tissues expressing high affinity G-protein coupled receptors (MT1 receptors). This nightly production of melatonin is essential for seasonal photoperiodic responses. The sites through which melatonin exerts these effects centre on the hypothalamus and pituitary, and in particular on the pituitary 'pars tuberalis' (PT), in which MT1 expression consistently exceeds that in all other tissues. Although there has been a tendency to associate the PT with intrapituitary effects of melatonin, this proposal develops the hypothesis that PT cells may actually relay the melatonin signal BACK INTO the brain. We propose that this occurs through local thyrotrophin (TSH) signalling, based on mapping of TSH and TSH-receptor expression in the PT and adjacent mediobasal hypothalamus. Importantly, TSH-receptor expression in the hypothalamus is localised to cells which have recently been implicated in seasonal modualtion of tri-iodothyronine (T3) levels in the hypothalamus. This occurs through their photoperiod-dependent expression of the enzyme deiodinase 2, which converts thyroxine (T4) to T3. Hence our proposal provides a mechanism to link hypothalamic T3 availability to the melatonin response in the PT. The project will test this by studying the molecular control of TSH expression in the PT, the importance of TSH-R signalling for expression of seasonal responses, and the extent to which changes in hypothalamic T3 account for, or can mimic seasonal responses.