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Evidence that TGFß May Directly Modulate POMC mRNA Expression in the Female Rat Arcuate Nucleus

INSERM U422 (S.B., M.T.V.C.-M., V.P., D.C., J.-C.B., V.M.), IFR 22, Laboratoire de Neuroendocrinologie et Physiopathologie Neuronale, 59045 Lille, France; Department of Anatomy and Brain Science (T.T.), Kobe University School of Medicine, Kobe 650-0017, Japan; and INSERM U413 (S.J., H.V.), IFRMP 23, Université de Rouen, 76821 Mont-Saint-Aignan, France

Address all correspondence and requests for reprints to: Dr. Sebastien Bouret, INSERM U422, 1 Place de Verdun, 59045 Lille Cedex, France. E-mail: bouret{at}lille.inserm.fr

The purpose of the present study was to determine whether TGFß, a cytokine secreted by hypothalamic astrocytes, was able to regulate POMC neurons in the arcuate nucleus. In a first set of experiments, mediobasal hypothalamic fragments were exposed to TGFß₁, and the relative POMC mRNA expression was assessed by in situ hybridization using a radiolabeled POMC riboprobe. The results showed that 4 x 10^-10 M TGFß₁ was efficient in decreasing significantly the amounts of POMC mRNA (P < 0.01). Interestingly, the decrease of relative POMC mRNA levels was higher in the rostral than in the caudal parts of the arcuate nucleus. In a second set of experiments, we examined the occurrence of TGFß receptors expression in arcuate POMC neurons. Dual labeling in situ hybridization and in situ hybridization, coupled to immunohistochemical labeling, were performed to examine mRNA expression of the type I serine-threonine kinase receptor for TGFß and the presence of type II receptor for TGFß, respectively, in POMC neurons. The results indicated that TGFß receptor I mRNA and TGFß receptor II protein were expressed in numerous POMC neurons. Regional analysis revealed that the highest proportion of POMC neurons expressing TGFß receptors was located in the rostral part of the arcuate nucleus. Using dual labeling immunohistochemistry, we also found that Smad2/3 immunoreactivity, a TGFß₁ downstream signaling molecule, was present in the cytoplasm and nucleus of some POMC (ß-endorphin) neurons. We next examined whether the number of POMC neurons expressing TGFß-RI mRNA was affected by sex steroids. Quantification of the number of POMC neurons expressing TGFß receptor I mRNA in ovariectomized, ovariectomized E2-treated, and ovariectomized E2 plus progesterone-treated animals revealed that estrogen treatment decreased the expression of TGFß receptor I mRNA in POMC neurons located in the rostral half of the arcuate nucleus, an effect reversed by progesterone in a subset of the most rostral cells. Taken together, these data reveal that TGFß₁ may directly modulate the activity of POMC neurons through the activation of TGFß receptors. Therefore, the present study provides additional evidence for the involvement of TGFß₁ in the regulation of neuroendocrine functions and supports the existence of a glial-to-neurons communication within the arcuate nucleus.

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