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Transforming Growth Factor ß₁ May Directly Influence Gonadotropin-Releasing Hormone Gene Expression in the Rat Hypothalamus

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 422, Institut Fédératif de Recherche 114, Unité de Neuroendocrinologie et de Physiopathologie Neuronale, 59045 Lille Cedex, France

Address all correspondence and requests for reprints to: Vincent Prevot, Ph.D., Institut National de la Santé et de la Recherche Médicale Unité 422, place de Verdun, 59045 Lille Cedex, France. E-mail: prevot{at}lille.inserm.fr.

In vitro studies using immortalized GT1 cells suggest that hypothalamic astrocytes employ TGFß₁ to directly regulate the secretion of GnRH, the neurohormone that controls sexual maturation and adult reproductive function. However, whether such astrocyte-GnRH neuron signaling occurs in vivo is not clear. In the present study, we used in situ hybridization and immunohistochemistry to determine whether astrocytes and GnRH neurons express the molecular components necessary to set in motion communication processes involving TGFß₁ signaling. Double-labeling experiments showed that astrocytes in the male rat preoptic region (POA) expressed TGFß₁ mRNA and that GnRH perikarya were often found in close association with TGFß₁ mRNA-expressing cells. In addition, GnRH neuronal cell bodies in the POA expressed both type II TGFß receptors (TGFß-RII), which selectively bind TGFß, and Smad2/3, one of the primary transducers of TGFß signaling, suggesting that they are fully capable of responding directly to TGFß₁ stimulation. Consistent with this hypothesis, incubation of POA explants with TGFß₁ caused a significant, dose-dependent decrease in GnRH mRNA expression in individual neurons. This effect was observed within 1 h after TGFß₁-treatment and was inhibited by addition of the soluble form of TGFß-RII to the incubation medium. In contrast, whereas both TGFß₁ and TGFß-RII mRNAs were abundantly expressed in both glial cells and capillaries in the median eminence, the projection field of GnRH neurons, TGFß-RII immunoreactivity was mainly restricted to the processes of tanycytes and did not colocalize with GnRH-immunoreactive fibers. This observation supports previous in vivo studies showing that TGFß₁ is unable to directly modulate decapeptide release from GnRH nerve terminals. Thus, astrocyte-derived TGFß₁ may directly influence GnRH expression and/or secretion in vivo by acting on the perikarya, but not the terminals, of GnRH neurons.