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The Transforming Growth Factor Alpha Gene Family Is Involved in the Neuroendocrine Control of Mammalian Puberty SR Ojeda, YJ Ma and F Rage

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The Transforming Growth Factor Alpha Gene Family Is Involved in the Neuroendocrine Control of Mammalian Puberty SR Ojeda, YJ Ma and F Rage Molecular Psychiatry (1997) 2, 355–358 1997 Stockton Press All rights reserved 1359–4184/97 $12.00 REVIEW ARTICLE: A TRIBUTE TO SM McCANN The transforming growth factor alpha gene family is involved in the neuroendocrine control of mammalian puberty SR Ojeda, YJ Ma and F Rage Division of Neuroscience, Oregon Regional Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006, USA The concept is proposed that the central control of mammalian female puberty requires the interactive participation of neuronal networks and glial cells of the astrocytic lineage. Accord- ing to this concept neurons and astrocytes control the pubertal process by regulating the secretory activity of those neurons that secrete luteinizing hormone-releasing hormone (LHRH). LHRH, in turn, governs sexual development by stimulating the secretion of pituitary gonadotropins. Astrocytes affect LHRH neuronal function via a cell–cell signaling mechanism involving several growth factors and their corresponding receptors. Our laboratory has ident- ified two members of the epidermal growth factor/transforming growth factor (EGF/TGFa) fam- ily as components of the glial-neuronal interactive process that regulates LHRH secretion. Transforming growth factor alpha (TGFa) and its distant congener neu-differentiation factor, NDF, are produced in hypothalamic astrocytes and stimulate LHRH release via a glial interme- diacy. The actions of TGFa and NDF on hypothalamic astrocytes involve the interactive acti- vation of their cognate receptors and the synergistic effect of both ligands in stimulating the glial release of prostaglandin E2 (PGE2). In turn, PGE2 acts directly on LHRH neurons to stimu- late LHRH release. A variety of experimental approaches has led to the conclusion that both TGFa and NDF are physiological components of the central mechanism controlling the initiation of female puberty. Keywords: glial cells; hypothalamus; growth factors; sexual development; astrocytes; cell–cell com- munication; LHRH neurons The onset of mammalian female puberty requires the ronal network is well-documented, recent studies have functional activation of a specialized group of hypo- raised the possibility that glial cells may also play a thalamic neurons that produce luteinizing hormone- role in the control of LHRH neuronal activity.9 Ana- releasing hormone (LHRH), the neurohormone govern- tomical evidence demonstrates that the glial ensheath- ing sexual maturation and reproductive function. ment of LHRH neurons in both primates and rodents Elucidation of the mechanisms controlling LHRH neu- is substantial,10,11 the main difference between species ronal function is critical for the understanding of the being a more prominent glial apposition to LHRH cellular and molecular processes underlying sexual perikarya in primates.10 Glial apposition of LHRH development and adult reproductive capacity. It is well nerve terminals in the median eminence of the hypo- accepted that transsynaptic inputs, both excitatory1,2 thalamus is, however, similarly abundant in both rats and inhibitory,3 contribute to the central regulation of and primates. The median eminence contains astro- LHRH secretion. A combination of a decrease in trans- cytes and modified ependymoglial cells known as tany- synaptic inhibitory tone and an increase in excitatory cytes.12 These specialized glial cells line the ventral inputs to LHRH neurons is thought to be instrumental portion of the third ventricle and send their processes in bringing about the initiation of puberty. The main towards the endothelial wall of the portal blood vascul- excitatory inputs affecting LHRH secretion include ature, establishing along their way intimate contact neuronal systems that utilize norepinephrine (NE),4 with LHRH nerve terminals.12,13 More intriguingly, sex neuropeptide Y (NPY)1 and excitatory amino acids.2,5,6 steroids appear to modulate this structural arrange- The inhibitory neurotransmitters, on the other hand, ment, as gonadectomy decreases the space between are gamma aminobutyric acid (GABA)3,7 and opioid LHRH nerve terminals and the basal lamina, presum- peptides.8 ably due to retraction of the glial cells.14 An obvious While this transsynaptic regulation of the LHRH neu- interpretation of these structural changes is that they increase the access of LHRH nerve endings to the portal vessels. The finding that about 50% of glial cells in 15 Correspondence: SR Ojeda, DVM, Division of Neuroscience, Ore- the median eminence have estrogen receptors further gon Regional Primate Research Center, 505 NW 185th Avenue, supports the notion of a direct action of estrogen on Beaverton, OR 97006, USA. E-mail: ojedasKohsu.edu hypothalamic astrocytes.16 As glial-neuronal synaptoid Glial growth factors and LHRH secretion SR Ojeda et al 356 specializations are commonly seen in the median emi- logical blockade of EGFR tyrosine kinase activity36 tar- nence,12 this region appears to be a primary site where geted to the median eminence delays the onset of glial cells influence LHRH neuronal function. In this puberty,23 suggesting that activation of EGFR in this article, we will discuss some of the recent results region of the hypothalamus is a physiological compo- obtained by our laboratory concerning the potentially nent of the central mechanism underlying the acqui- important role played by glial cells in the regulation of sition of reproductive competence. In another study, LHRH secretion. we asked the question as to whether focal activation In a series of reports, we documented the concept of TGFa secretion would be able to stimulate LHRH that glia-derived transforming growth factor alpha neuronal activity, and thus accelerate the onset of (TGFa), a mitogenic polypeptide member of the epider- puberty. To produce this focal increase we used two mal growth factor (EGF) family,17–19 plays an important gene delivery systems. In one of them, fibroblasts were role in the process by which astrocytes affect LHRH stably transfected with a retroviral construct in which secretory activity.16,20–24 More recently, we obtained expression of the human TGFa gene was directed by evidence for the involvement of other members of the the phosphoglycerate kinase promoter, which is consti- EGF/TGFa family in this process. Neuregulins, also tutively active in most mammalian cells. The other known as heregulins25 or—in the case of the rat—as delivery system consisted of a plasmid construct in neu-differentiation factor (NDF),26 are alternatively which the human TGFa gene was placed under the spliced products of a single gene.26,27 Our studies control of a mouse MT promoter. Since this promoter showed that NDF is produced in hypothalamic astro- is activated by heavy metals, TGFa expression can be cytes and facilitates LHRH release through a mech- increased several-fold by simply exposing the cells car- anism involving stimulation of glial PGE2 release and rying the construct to zinc chloride. facilitation of TGFa action on astrocytes (Ma et al, The genetically modified fibroblasts were then unpublished). implanted into different hypothalamic sites of juvenile The biological actions of TGFa and NDF are initiated female rats and the onset of puberty was evaluated. To by binding to membrane-spanning receptors endowed activate a circadian expression of the TGFa gene con- with protein kinase activity for cellular signaling.28–32 trolled by the MT promoter, animals bearing these cells The receptor for TGFa (which also recognizes EGF, were injected once daily with zinc chloride. The amphiregulins and other related members of the results demonstrated that cells carrying either con- family) is a 170-kDa glycosylated protein known as the struct were able to accelerate the onset of puberty only EGF receptor (EGFR). EGFR has an extracellular when they were grafted in the immediate vicinity of domain containing the amino acid motifs essential for LHRH neurons. The effect appears to be more robust ligand recognition, a single transmembrane domain, when the cells were located in contact with LHRH and an intracellular domain endowed with tyrosine nerve terminals in the median eminence of the hypo- kinase activity. The receptors for NDF, known as HER- thalamus.37 Thus, these experiments demonstrate that 3 (also named ERBB-3)29,31 and HER-4,30 are related to a localized activation of TGFa production can acceler- EGFR. An additional related receptor, known as HER- ate puberty, as long as the activation occurs within the 2 (neu) receptor,32,33 appears to function as an auxiliary confines of the LHRH neuron microenvironment. subunit for the high affinity binding of TGFa/EGF to As indicated before, TGFa is not the only member of EGFR and NDF/neuregulins to HER-3 and HER-4.34 the EGF family that participates in the control of LHRH In the hypothalamus of both rats23 and nonhuman secretion. In very recent in vitro experiments we found primates,20 the TGFa gene and its protein product are that glia-derived NDF enhances the stimulatory action predominantly expressed in astroglial cells of certain of TGFa on LHRH release via activation of an HER- nuclei, such as the suprachiasmatic nucleus, arcuate 2/HER-4 receptor complex. Blockade of NDF signal nucleus and dorsomedial nucleus.23 Both TGFa mRNA transduction via an antisense oligonucleotide, which and protein are also abundant in tanycytes and glial disrupts the synthesis of HER-2, also attenuated the cells of the median eminence, the level of expression effect of TGFa on LHRH release indicating that the increasing significantly around the
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