This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. These studies examine the role that cell-cell communication within the brain plays in the control of female puberty. The concept is being developed that reciprocal communication between neurons (one of the two main functional and structural units of the central nervous system) and astroglial cells (the other main building block of the nervous system) is critical for the timely acquisition of female sexual maturity and reproductive competence. We have identified several components of this glia-neuron regulatory system and elucidated some of the intercellular mechanisms they employ to transfer information from astroglial cells to the neurons that secrete luteinizing hormone-releasing hormone (LHRH), the hormone controlling female sexual development. A family of growth factors related to a protein known as epidermal growth factor (EGF) was found to be produced by astroglial cells and to function interactively to facilitate LHRH secretion and, thus, regulate the initiation of the pubertal process. Using mutant mice in which the normal function of these pivotal recognition molecules mediating the actions of EGF-related proteins was impaired, we demonstrated that these astroglial-derived growth factors are required for normal female sexual development. We have also used genomic and proteomic approaches to identify new genes that, expressed in the hypothalamus, participate in the control of the pubertal process. Altogether these results reveal an extraordinary complexity in the regulatory process used by the brain to control sexual development in mammals, and provide support for the concept that the syndromes of sexual precocity and delayed sexual development of central origin in humans may be related to abnormalities affecting these major regulatory pathways.
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