PI: Gore, A. Proposal Number: IBN-9723398 The overall goal of this research proposal is to characterize the development of the gonadotropin-releasing hormone (GnRH) neurosecretory system in the mouse, and to study the maturation of these cells using a cell line model. GnRH is the key hormone regulating reproduction; it is produced in neurons whose cell bodies reside in the preoptic area anterior-hypothalamus (POA-AH) of rodent brains. This peptide hormone is released into blood vessels which project to the pituitary gland; there, GnRH stimulates synthesis and release of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These latter hormones in turn affect the synthesis and secretion of ovarian and testicular steroid hormones. The release of GnRH changes developmentally, particularly at birth and puberty, and an increase in pulsatile GnRH release is the critical factor for the onset of puberty. Because the GnRH neurosecretory system is already established before birth, it is believed that changes in inputs to GnRH neurons are responsible for the alterations in GnRH synthesis and release that occur during development. Growth factors produced by glia (non-neuronal elements in the brain) such as insulin-like growth factor-1 (IGF-1) appear to play an important role in the changes in GnRH release and biosynthesis that occur during development. It is the intention of this proposal to characterize the molecular and anatomical changes in the GnRH system in relation to the IGF-1 system during the early developmental period. In Aim 1, the role of IGF-1 on GnRH biosynthesis will be studied in developing male and female mice. The anatomical relationship between GnRH neurons and IGF-1-producing glia will also be ascertained. A mutant mouse strain which lacks IGF-1 (the IGF-1 knockouts) will be evaluated as to the effects of the absence of IGF-1 on hypothalamic development. In Aim 2, the immortalized hypothalamic GT1-7 cell line, which synthesizes and secretes G nRH, will be used to examine the effects of IGF-1 on the "maturation" of these immature cells. It is the intention of this Aim to make the GT1-7 cells more like a normal GnRH neuron in the brain. Data provided by these studies should provide insights into the role of the neurotrophic factor IGF-1 in the development of the GnRH system which ultimately results in the onset of reproductive maturation. The results should also lead to a better understanding of the general mechanisms by which brain development occurs and is regulated.
