These studies have shown that hypothalamic astrocytes contribute to the central mechanism controlling the initiation of mammalian puberty. They do so via glia-to-neuron communication pathways initiated by at least two members of the epidermal growth factor (EGF) family of growth factors, transforming growth factor alpha (TGF?) and neuregulins (NRGs), produced in astrocytes. At puberty, hypothalamic synthesis of TGF? increases, becoming maximal on the day of the first preovulatory surge of gonadotropins. The increase in TGF? gene expression occurs in the absence of augmented levels of the TGF? receptor, erbB-1, but it is accompanied by enhanced synthesis of erbB-4 and erbB-2, two of the NRG receptors expressed in hypothalamic astrocytes. Hypothalamic expression of both of these receptors first increases, in a gonadal -independent manner, during late juvenile development, and then stimulated by gonadal steroids, at the time of puberty. Ligand-dependent activation of hypo thalamic erbB-1 or erbB-4 receptors results in recruitment of the auxiliary receptor erbB-2, indicating that this molecule is an intrinsic component of the signaling cascade by which TGF? and NRGs affect hypothalamic function. Blockade of erbB-2 synthesis via antisense oligodeoxynucleotides revealed that the erbB-2 receptor is, indeed, required for both erbB-1 and erbB-4-mediated signaling in hypothalamic astrocytes, and is essential for the timely initiation of puberty. Grafting of TGF?-producing cells near LHRH neurons accelerated the initiation of puberty, indicating that a focal increase in the availability of this growth factor suffices to activate the LHRH neuronal network and initiate puberty. Examination of two human hypothalamic hamartomas associated with extreme acceleration of female sexual development supported this view by showing the presence of a profuse network of TGF?-producing astrocytes in both cases. Other studies identified Oct-2, a homeodomain gene, as one of the upstream transcriptional regulators of TGF? and erbB-2 expression in the developing hypothalamus. DNA fragments corresponding to portions of the genes encoding neuregulins and their erbB receptors in the rhesus monkey have been cloned and are being used to examine the developmental profile of these genes in the monkey hypothalamus. FUNDING NIH HD25123 PUBLICATIONS Jung H, Shannon EM, Fritschy J-M, Ojeda SR. Several GABAA receptor subunits are expressed in LHRH neurons of juvenile female rats. Brain Res 780:218-229, 1998. Ojeda SR, Ma YJ. Epidermal growth factor tyrosine kinase receptors and the neuroendocrine control of mammalian puberty. Mol Cell Endocrinol 140:101-106, 1998. Ojeda SR, Ma YJ, Rage F. Glial growth factors acting via tyrosine kinase receptors contribute to the neuroendocrine control of female puberty. In Pennington Center Nutrition Series Vol. 8 Nutrition and Reproduction (Bray GA, Ryan DH, eds). Baton Rouge, LA Louisiana State University Press, pp 81-94, 1998. Ojeda SR, Hill JK, Hill DF, Ma YJ. The oct-2 POU-domain gene A transcriptional regulator of mammalian puberty. In Endocrine Society Program and Abstracts 80th Annual Meeting (held in New Orleans, LA, June 24-27, 1998), p 523 (abstract #P3-671). Ma YJ, Jung H, Ojeda SR. A glutamate-gamma aminobutyric acid (GABA) connection in the control of luteinizing hormone-releasing hormone (LHRH) release via metabotropic glutamate receptor (mGluR). Soc Neurosci Abstr 24:1855, 1998 (abstract #736.11).
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