NEUROENDOCRINOLOGY OF PUBERTY AND SEXUAL DEVELOPMENT

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This is an application aimed at elucidating the neuroendocrine mechanisms involved in controlling the initiation of mammalian puberty. Since the inception of the original proposal, as part of a program project in 1977, we have made steady progress towards this goal, first delineating the roles that different pituitary and gonadal hormones play in the control of female sexual development, then defining the contribution of steroid feedback mechanisms to the developmental regulation of gonadotropin release, and later, characterizing the signal transduction pathways involved in the process of neurotransmitter-induced LHRH release at puberty. Further studies led to the conclusion-that LHRH neurons themselves do not constitute a limiting factor for puberty to occur, and that an activation of excitatory inputs to LHRH neurons is a primary mechanism contributing to the onset of female puberty. These and other observations made dear that efforts had to be devoted to identifying "upstream' molecular components that, operating within the brain, determine the initiation of the pubertal process. During the last period of support, we obtained evidence implicating transforming growth factor alpha (TURK.), a member of the epidermal growth factor (EGF) family, as one of these components. Identification of glial cells of the astrocytic lineage as the main source of TGFalpha synthesis, led to additional studies that suggested the existence of neuronal glial interactive events and the participation of glial-derived molecules in the developmental control of LHRH neuronal function. The present application proposes studies to firmly define the nature and the physiological importance of these interactions. It also intends to identify a higher level of hierarchy in the neuroendocrine cascade that controls the onset of puberty by characterizing the potential involvement of a regulatory homeobox- encoding gene in the control of the pubertal process. To this end, the following aims are proposed: 1) To examine the hypothesis that glial TGF- alpha stimulates LHRH release indirectly by eliciting prostaglandin E (PGE2) release from astrocytes and by selectively upregulating, also via glial intermediacy, the expression of PGE2 receptor genes linked to Ca2+ mobilization and/or cyclic AMP formation in LHRH neurons. 2) To examine the that TGF-alpha gene expression in hypothalamic astrocytes is not only upregulated by paracrine/autocrine influences of glial origin, but also by some of the same neurotransmitter inputs known to stimulate LHRH secretion at puberty. 3) To examine the hypothesis that other members of the EGF/TGR-alpha family interact collaboratively with TGF-alpha in the control of LHRH neuronal function, and 4) To examine the hypothesis that Oct-2, a homeobox-containing gene of the POU-domain gene family recently found in the hypothalamus of female rats undergoing lesion-induced sexual precocity, contributes to the transcriptional activation of the TGF-alpha gene and, hence, represents one of the upstream regulatory genes controlling the onset of puberty.