Identification of Melatonin-Regulated Genes in the Ovine Pituitary Pars Tuberalis, a Target Site for Seasonal Hormone Control

The pars tuberalis (PT) of the pituitary gland expresses a high density of melatonin (MEL) receptors and is believed to regulate seasonal physiology by decoding changes in nocturnal melatonin secretion. Circadian clock genes are known to be expressed in the PT in response to the decline (Per1) and onset (Cry1) of MEL secretion, but to date little is known of other molecular changes in this key MEL target site. To identify transcriptional pathways that may be involved in the diurnal and photoperiod-transduction mechanism, we performed a whole genome transcriptome analysis using PT RNA isolated from sheep culled at three time points over the 24-h cycle under either long or short photoperiods. Our results reveal 153 transcripts where expression differs between photoperiods at the light-dark transition and 54 transcripts where expression level was more globally altered by photoperiod (all time points combined). Cry1 induction at night was associated with up-regulation of genes coding for NeuroD1 (neurogenic differentiation factor 1), Pbef/Nampt( nicotinamide phosphoribosyltransferase), Hif1 alpha (hypoxia-inducible factor-1 alpha), and Kcnq5 (K+ channel) and down-regulation of Ror beta, a key clock gene regulator. Using in situ hybridization, we confirmed day-night differences in expression for Pbef/Nampt, NeuroD1, and Ror beta in the PT. Treatment of sheep with MEL increased PT expression for Cry1, Pbef/Nampt, NeuroD1, and Hif1 alpha, but not Kcnq5. Our data thus reveal a cluster of Cry1-associated genes that are acutely responsive to MEL and novel transcriptional pathways involved in MEL action in the PT. (Endocrinology 149: 5527-5539, 2008)