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J Neuroendocrinol. 2003 Apr;15(4):390-7.

Clock genes and the long-term regulation of prolactin secretion: evidence for a photoperiod/circannual timer in the pars tuberalis.

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MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, Scotland, UK.


Prolactin secretion is regulated by photoperiod through changes in the 24-h melatonin profile and displays circannual rhythmicity under constant photoperiod. These two processes appear to occur principally within the pituitary gland, controlled by the pars tuberalis. This is evident because: (i) hypothalamic-pituitary disconnected (HPD) sheep show marked changes in prolactin secretion in response to switches in photoperiod and manipulations of melatonin, similar to brain-intact controls; (ii) HPD sheep also show photoperiod-specific, long-term cycles in prolactin secretion under constant long or short days, with the timing maintained even when prolactin secretion is blocked for 2-3 months; and (iii) pars tuberalis cells, but not lactotrophs, express high concentrations of melatonin (MT1) receptor, and exhibit a duration-sensitive, cAMP-dependant, inhibitory response to physiological concentrations of melatonin. This suggests the existence of an intrinsic, reversible photoperiod-circannual timer in pars tuberalis cells. A full complement of clock genes (Bmal1, Clock, Per1, Per2, Cry1 and Cry2) are expressed in the ovine pars tuberalis, and undergo 24-h cyclical expression as observed in a cell autonomous, circadian clock. Activation of Per genes occurs in the early day (melatonin off-set), while activation of Cry genes occurs in the early night (melatonin on-set). This temporal association is evident under both long and short days, thus the Per-Cry interval varies directly with photoperiod. Because, PER : CRY, protein : protein interactions affect stability, nuclear entry and gene transcription based on rodent data, the change in phasing of Per/Cry expression provides a potential mechanism for decoding the long day/short day melatonin signal. A speculative, but testable, extension of this hypothesis is that intrinsically regulated changes in the phase of Per/Cry rhythms, regulates both photorefractoriness and the generation of circannual rhythms in prolactin secretion.

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