This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ma, Y. J. Articles by Ojeda, S. R. Search for Related Content PubMed PubMed Citation Articles by Ma, Y. J. Articles by Ojeda, S. R.

Hypothalamic Astrocytes Respond to Transforming Growth Factor- with the Secretion of Neuroactive Substances That Stimulate the Release of Luteinizing Hormone-Releasing Hormone¹

Division of Neuroscience, Oregon Regional Primate Research Center, Oregon Health Sciences University (Y.J.M., K.B.E., F.R., S.R.O.), Beaverton, Oregon 97006; and the Laboratory of Cell and Molecular Pharmacology, National Institute of Environmental and Health Science (W.C.W.), Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Dr. Sergio R. Ojeda, Division of Neuroscience, Oregon Regional Primate Research Center, Oregon Health Sciences University, 505 NW 185th Avenue, Beaverton, Oregon 97006.

Previous studies demonstrated the involvement of transforming growth factor- (TGF), a member of the epidermal growth factor (EGF) family, in the developmental regulation of hypothalamic LHRH release. Although both TGF and EGF stimulate LHRH release, they do not appear to act directly on LHRH neurons, as no EGF/TGF receptors are detected on these cells in vivo. Instead, the stimulatory effect of TGF on LHRH release seems to require a glial intermediacy. The present study identifies one of the glial molecules involved in this process. In vitro exposure of purified hypothalamic astrocytes to TGF or EGF in a defined medium led to activation of the cyclooxygenase-mediated pathway of arachidonic acid metabolism, as indicated by an increase in PGE₂ release, but failed to affect lipooxygenase-mediated metabolism, as assessed by the lack of increase in leukotriene C4 production; addition of TGF- (T-CM) or EGF-conditioned medium to cultures of LHRH-producing GT1-1 cells stimulated LHRH release. In contrast, direct exposure of GT1-1 cells to the growth factors was ineffective. Incubation of the cells in medium conditioned by untreated astrocytes (CM) was also ineffective. Blockade of either EGF receptor signal transduction or cyclooxygenase activity in the astrocytic cultures prevented both TGF-induced PGE₂ formation in astrocytes and the stimulatory effect of T-CM on LHRH release. Immunoneutralization of PGE₂ actions or selective removal of the PG from T-CM also prevented T-CM-induced LHRH release. Addition of exogenous PGE₂ restored the effect. Thus, PGE₂ is one of the glial molecules involved in mediating the stimulatory effect of TGF on LHRH release. The effectiveness of PGE₂ in eliciting LHRH release was, however, greatly reduced when PG was delivered to GT1-1 cells in astrocyte-defined medium instead of CM. Thus, astrocytes appear to produce a yet to be identified substance(s) that facilitates the stimulatory effect of PGE₂ on LHRH output. We postulate that the ability of TGF to enhance LHRH release depends on the potentiating interaction of PGE₂ with these additional glial-derived molecules.

This article has been cited by other articles:

				A.-S. Parent, G. Rasier, V. Matagne, A. Lomniczi, M.-C. Lebrethon, A. Gerard, S. R. Ojeda, and J.-P. Bourguignon Oxytocin Facilitates Female Sexual Maturation through a Glia-to-Neuron Signaling Pathway Endocrinology, March 1, 2008; 149(3): 1358 - 1365. [Abstract] [Full Text] [PDF]

				T. Takagi, T. Yamamura, T. Anraku, S. Yasuo, N. Nakao, M. Watanabe, M. Iigo, S. Ebihara, and T. Yoshimura Involvement of Transforming Growth Factor {alpha} in the Photoperiodic Regulation of Reproduction in Birds Endocrinology, June 1, 2007; 148(6): 2788 - 2792. [Abstract] [Full Text] [PDF]

				S. R. Ojeda, A. Lomniczi, C. Mastronardi, S. Heger, C. Roth, A.-S. Parent, V. Matagne, and A. E. Mungenast Minireview: The Neuroendocrine Regulation of Puberty: Is the Time Ripe for a Systems Biology Approach? Endocrinology, March 1, 2006; 147(3): 1166 - 1174. [Abstract] [Full Text] [PDF]

				C. M. Gammon, G. M. Freeman Jr., W. Xie, S. L. Petersen, and W. C. Wetsel Regulation of Gonadotropin-Releasing Hormone Secretion by Cannabinoids Endocrinology, October 1, 2005; 146(10): 4491 - 4499. [Abstract] [Full Text] [PDF]

				V. Matagne, M.-C. Lebrethon, A. Gerard, and J.-P. Bourguignon Kainate/Estrogen Receptor Involvement in Rapid Estradiol Effects in Vitro and Intracellular Signaling Pathways Endocrinology, May 1, 2005; 146(5): 2313 - 2323. [Abstract] [Full Text] [PDF]

				V. Prevot, A. Lomniczi, G. Corfas, and S. R. Ojeda erbB-1 and erbB-4 Receptors Act in Concert to Facilitate Female Sexual Development and Mature Reproductive Function Endocrinology, March 1, 2005; 146(3): 1465 - 1472. [Abstract] [Full Text] [PDF]

				V. Prevot, A. Cornea, A. Mungenast, G. Smiley, and S. R. Ojeda Activation of erbB-1 Signaling in Tanycytes of the Median Eminence Stimulates Transforming Growth Factor {beta}1 Release via Prostaglandin E2 Production and Induces Cell Plasticity J. Neurosci., November 19, 2003; 23(33): 10622 - 10632. [Abstract] [Full Text] [PDF]

				B. Li, Z. Yang, J. Hou, A. McCracken, M. A. Jennings, and M. Y. J. Ma Compromised Reproductive Function in Adult Female Mice Selectively Expressing Mutant ErbB-1 Tyrosine Kinase Receptors in Astroglia Mol. Endocrinol., November 1, 2003; 17(11): 2365 - 2376. [Abstract] [Full Text] [PDF]

				K. M. Dhandapani, V. B. Mahesh, and D. W. Brann Astrocytes and Brain Function: Implications for Reproduction Experimental Biology and Medicine, March 1, 2003; 228(3): 253 - 260. [Abstract] [Full Text] [PDF]

				B. Dziedzic, V. Prevot, A. Lomniczi, H. Jung, A. Cornea, and S. R. Ojeda Neuron-to-Glia Signaling Mediated by Excitatory Amino Acid Receptors Regulates ErbB Receptor Function in Astroglial Cells of the Neuroendocrine Brain J. Neurosci., February 1, 2003; 23(3): 915 - 926. [Abstract] [Full Text] [PDF]

				V. Prevot, C. Rio, G. J. Cho, A. Lomniczi, S. Heger, C. M. Neville, N. A. Rosenthal, S. R. Ojeda, and G. Corfas Normal Female Sexual Development Requires Neuregulin-erbB Receptor Signaling in Hypothalamic Astrocytes J. Neurosci., January 1, 2003; 23(1): 230 - 239. [Abstract] [Full Text] [PDF]

				S. K. Amateau and M. M. McCarthy A Novel Mechanism of Dendritic Spine Plasticity Involving Estradiol Induction of Prostaglandin-E2 J. Neurosci., October 1, 2002; 22(19): 8586 - 8596. [Abstract] [Full Text] [PDF]

				S. R. Chiocchio, M. G.P. Gallardo, P. Louzan, V. Gutnisky, and J. H. Tramezzani Melanin-Concentrating Hormone Stimulates the Release of Luteinizing Hormone-Releasing Hormone and Gonadotropins in the Female Rat Acting at Both Median Eminence and Pituitary Levels Biol Reprod, May 1, 2001; 64(5): 1466 - 1472. [Abstract] [Full Text]

				E. Terasawa and D. L. Fernandez Neurobiological Mechanisms of the Onset of Puberty in Primates Endocr. Rev., February 1, 2001; 22(1): 111 - 151. [Abstract] [Full Text]

				C. D. Buchanan, V. B. Mahesh, and D. W. Brann Estrogen-Astrocyte-Luteinizing Hormone-Releasing Hormone Signaling: A Rolefor Transforming Growth Factor-{beta}1 Biol Reprod, June 1, 2000; 62(6): 1710 - 1721. [Abstract] [Full Text]

				T. G. Harris, D. F. Battaglia, M. E. Brown, M. B. Brown, N. E. Carlson, C. Viguie, C. Y. Williams, and F. J. Karsch Prostaglandins Mediate the Endotoxin-Induced Suppression of Pulsatile Gonadotropin-Releasing Hormone and Luteinizing Hormone Secretion in the Ewe Endocrinology, March 1, 2000; 141(3): 1050 - 1058. [Abstract] [Full Text] [PDF]

				K. J. Suter, C. R. Pohl, and M. E. Wilson Circulating Concentrations of Nocturnal Leptin, Growth Hormone, and Insulin-Like Growth Factor-I Increase before the Onset of Puberty in Agonadal Male Monkeys: Potential Signals for the Initiation of Puberty J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 808 - 814. [Abstract] [Full Text]

				Some Hypothalamic Hamartomas Contain Transforming Growth Factor {alpha}, a Puberty-Inducing Growth Factor, But Not Luteinizing Hormone-Releasing Hormone Neurons J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4695 - 4701. [Abstract] [Full Text]

				Y. J. Ma, D. F. Hill, K. E. Creswick, M. E. Costa, A. Cornea, M. N. Lioubin, G. D. Plowman, and S. R. Ojeda Neuregulins Signaling via a Glial erbB-2-erbB-4 Receptor Complex Contribute to the Neuroendocrine Control of Mammalian Sexual Development J. Neurosci., November 15, 1999; 19(22): 9913 - 9927. [Abstract] [Full Text] [PDF]

				S. R. Ojeda, J. Hill, D. F. Hill, M. E. Costa, V. Tapia, A. Cornea, and Y. J. Ma The Oct-2 POU Domain Gene in the Neuroendocrine Brain: A Transcriptional Regulator of Mammalian Puberty Endocrinology, August 1, 1999; 140(8): 3774 - 3789. [Abstract] [Full Text]

				M. O. HEBB, E. M. DENOVAN-WRIGHT, and H. A. ROBERTSON Expression of the Huntington's disease gene is regulated in astrocytes in the arcuate nucleus of the hypothalamus of postpartum rats FASEB J, June 1, 1999; 13(9): 1099 - 1106. [Abstract] [Full Text]

				V. Prevot, D. Croix, C. M. Rialas, P. Poulain, G. L. Fricchione, G. B. Stefano, and J.-C. Beauvillain Estradiol Coupling to Endothelial Nitric Oxide Stimulates Gonadotropin-Releasing Hormone Release from Rat Median Eminence Via a Membrane Receptor Endocrinology, February 1, 1999; 140(2): 652 - 659. [Abstract] [Full Text]

				F. Pimpinelli, G. E. Rovati, V. Capra, F. Piva, L. Martini, and R. Maggi Expression of Prostacyclin Receptors in Luteinizing Hormone-Releasing Hormone Immortalized Neurons: Role in the Control of Hormone Secretion Endocrinology, January 1, 1999; 140(1): 171 - 177. [Abstract] [Full Text]

				A. G. Rabchevsky, J. M. Weinitz, M. Coulpier, C. Fages, M. Tinel, and M.-P. Junier A Role for Transforming Growth Factor alpha  as an Inducer of Astrogliosis J. Neurosci., December 15, 1998; 18(24): 10541 - 10552. [Abstract] [Full Text] [PDF]

				A. E. Herbison Multimodal Influence of Estrogen upon Gonadotropin-Releasing Hormone Neurons Endocr. Rev., June 1, 1998; 19(3): 302 - 330. [Abstract] [Full Text]

				A. N. Harris and P. L. Mellon The Basic Helix-Loop-Helix, Leucine Zipper Transcription Factor, USF (Upstream Stimulatory Factor), Is a Key Regulator of SF-1 (Steroidogenic Factor-1) Gene Expression in Pituitary Gonadotrope and Steroidogenic Cells Mol. Endocrinol., May 1, 1998; 12(5): 714 - 726. [Abstract] [Full Text]

				Y. Ren, T. Satoh, M. Yamada, K. Hashimoto, S. Konaka, T. Iwasaki, and M. Mori Stimulation of the Preprothyrotropin-Releasing Hormone Gene by Epidermal Growth Factor Endocrinology, January 1, 1998; 139(1): 195 - 203. [Abstract] [Full Text] [PDF]

				F. Rage, B. J. Lee, Y. J. Ma, and S. R. Ojeda Estradiol Enhances Prostaglandin E2 Receptor Gene Expression in Luteinizing Hormone-Releasing Hormone (LHRH) Neurons and Facilitates the LHRH Response to PGE2 by Activating a Glia-to-Neuron Signaling Pathway J. Neurosci., December 1, 1997; 17(23): 9145 - 9156. [Abstract] [Full Text] [PDF]

				F. Rage, D. F. Hill, M. Sena-Esteves, X. O. Breakefield, R. J. Coffey, M. E. Costa, S. M. McCann, and S. R. Ojeda Targeting transforming growth factor alpha  expression to discrete loci of the neuroendocrine brain induces female sexual precocity PNAS, March 18, 1997; 94(6): 2735 - 2740. [Abstract] [Full Text] [PDF]