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

J Neuroendocrinol. 2003 Apr;15(4):390-7. doi: 10.1046/j.1365-2826.2003.00990.x.


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Biological Clocks / physiology*
  • Biological Clocks / radiation effects
  • CLOCK Proteins
  • Cricetinae
  • Cryptochromes
  • Drosophila Proteins*
  • Eye Proteins*
  • Flavoproteins / genetics
  • Gene Expression Regulation / physiology*
  • Gene Expression Regulation / radiation effects
  • Hypothalamo-Hypophyseal System / physiopathology
  • Light
  • Melatonin / physiology*
  • Models, Biological
  • Nuclear Proteins / genetics
  • Photoperiod*
  • Photoreceptor Cells, Invertebrate*
  • Pituitary Gland, Anterior / metabolism*
  • Prolactin / metabolism*
  • Receptors, G-Protein-Coupled
  • Seasons
  • Sheep / physiology
  • Suprachiasmatic Nucleus / physiology
  • Suprachiasmatic Nucleus / radiation effects
  • Trans-Activators / genetics


  • CRY1 protein, human
  • CRY2 protein, human
  • Cryptochromes
  • Drosophila Proteins
  • Eye Proteins
  • Flavoproteins
  • Nuclear Proteins
  • Receptors, G-Protein-Coupled
  • Trans-Activators
  • cry protein, Drosophila
  • Prolactin
  • CLOCK Proteins
  • CLOCK protein, human
  • Melatonin