Clock genes and the long-term regulation of prolactin secretion: evidence for a photoperiod/circannual timer in the pars tuberalis.
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.
Lincoln
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GA
MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, Scotland, UK. g.lincoln@hrsu.mrc.ac.uk
Andersson
H
H
Hazlerigg
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D
D000818:Animals; D001683:Biological Clocks / Q000502:physiology* / Q000528:radiation effects; D056926:CLOCK Proteins; D006224:Cricetinae; D056931:Cryptochromes; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology* / Q000528:radiation effects; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D008027:Light; D008550:Melatonin / Q000502:physiology*; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics; D017440:Photoperiod; D017956:Photoreceptor Cells, Invertebrate; D010903:Pituitary Gland, Anterior / Q000378:metabolism*; D011388:Prolactin / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D012621:Seasons; D012756:Sheep / Q000502:physiology; D013493:Suprachiasmatic Nucleus / Q000502:physiology / Q000528:radiation effects; D015534:Trans-Activators / Q000235:genetics
C538963:CRY1 protein, human; C538966:CRY2 protein, human; D056931:Cryptochromes; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins; D009687:Nuclear Proteins; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; C119828:cry protein, Drosophila; D011388:Prolactin; D056926:CLOCK Proteins; C538943:CLOCK protein, human; D008550:Melatonin