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Developmental and Diurnal Dynamics of Pax4 Expression in the Mammalian Pineal Gland: Nocturnal Down-Regulation Is Mediated by Adrenergic-Cyclic Adenosine 3',5'-Monophosphate Signaling

Department of Neuroscience and Pharmacology (M.F.R., M.M.), University of Copenhagen, DK-2200 Copenhagen, Denmark; Section on Neuroendocrinology (M.F.R., M.J.B., J.-S.K., P.G., S.L.C., D.C.K.), Program in Developmental Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Department of Poultry Science (M.J.B.), Texas A&M University, College Station, Texas 77843; and Department of Physiology (A.K.H.), University of Alberta, Edmonton, AB, Canada T6G 2H7

Address all correspondence and requests for reprints to: Martin Fredensborg Rath, Department of Neuroscience and Pharmacology, University of Copenhagen, Panum Institute 24.3, Blegdamsvej 3, DK-2200 Copenhagen, Denmark. E-mail: mrath{at}sund.ku.dk.

Pax4 is a homeobox gene that is known to be involved in embryonic development of the endocrine pancreas. In this tissue, Pax4 counters the effects of the related protein, Pax6. Pax6 is essential for development of the pineal gland. In this study we report that Pax4 is strongly expressed in the pineal gland and retina of the rat. Pineal Pax4 transcripts are low in the fetus and increase postnatally; Pax6 exhibits an inverse pattern of expression, being more strongly expressed in the fetus. In the adult the abundance of Pax4 mRNA exhibits a diurnal rhythm in the pineal gland with maximal levels occurring late during the light period. Sympathetic denervation of the pineal gland by superior cervical ganglionectomy prevents the nocturnal decrease in pineal Pax4 mRNA. At night the pineal gland is adrenergically stimulated by release of norepinephrine from the sympathetic innervation; here, we found that treatment with adrenergic agonists suppresses pineal Pax4 expression in vivo and in vitro. This suppression appears to be mediated by cAMP, a second messenger of norepinephrine in the pineal gland, based on the observation that treatment with a cAMP mimic reduces pineal Pax4 mRNA levels. These findings suggest that the nocturnal decrease in pineal Pax4 mRNA is controlled by the sympathetic neural pathway that controls pineal function acting via an adrenergic-cAMP mechanism. The daily changes in Pax4 expression may influence gene expression in the pineal gland.