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Submitted on June 24, 2005
Accepted on August 17, 2005
Centre for Neuroendocrinology and Department of Anatomy and Structural Biology, School of Medical Sciences, The University of Otago (F.Y.M., G.M.A., T.D.G., D.R.G. S.J.B) Dunedin, New Zealand and INSERM, U-584, Molecular Endocrinology, Faculté de Médecine Necker (V.G.) 156 rue de Vaugirard, 75730 Paris, France
* To whom correspondence should be addressed. E-mail: stephen.bunn{at}stonebow.otago.ac.nz.
The hypothalamic neuroendocrine dopaminergic (NEDA) neurons are crucial in regulating prolactin secretion from the anterior pituitary. Rising prolactin concentrations stimulate these neurons to secrete dopamine, which acts via the pituitary portal vasculature to inhibit further prolactin release. Prolactin is known to activate JAK-STAT signaling pathways in other cell-types, including neurons. The possible role of JAK-STAT signaling in NEDA neurons has therefore been examined here using fetal rat mediobasal hypothalamic cell cultures and an adult rat in vivo preparation. Cultured cells expressing the dopamine synthesizing enzyme tyrosine hydroxylase (TH) responded to prolactin with a time-dependent increase in phospho-STAT5 but not phospho-STAT1 or phospho-STAT3 nuclear labeling. This response was inhibited by the prolactin receptor antagonist 
1-9-G129R-hPRL and the JAK inhibitor AG490 but was unaffected by selected serine/threonine kinase inhibitors (H89, KN-93, bisindolymaleimide or PD98059). Antibodies selective for STAT5a or STAT5b indicated that the response was restricted to STAT5b, with the number of TH cells displaying STAT5b nuclear immunoreactivity rising from <10% under basal conditions to approximately 70% following prolactin stimulation. STAT5a nuclear labeling remained unchanged at 6-10% of TH positive cells. STAT5b selectivity was confirmed in vivo where injection of prolactin into bromocriptine-treated rats stimulated a time-dependent increase in STAT5b but not STAT5a nuclear staining in the TH expressing neurons in the arcuate nucleus. These results extend our previous findings with STAT5b-deficient mice and strongly suggest that in NEDA neurons prolactin signaling via the JAK/STAT pathway is mediated exclusively by STAT5b.
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