The overall goal of the proposed studies is to determine how the steroid hormone estrogen and the neurotrophin family of growth factors collaborate in the differentiation and survival of CNS neurons. Overlapping regions of the forebrain are targets of estrogen and neurotrophins, as well as sites of estrogen and neurotrophin synthesis. This suggests that interactions of estrogen with neurotrophins may be essential for the differentiation and development of target neurons. The proposed studies investigate the biological and functional significance of our observations of (a) co-localization of estrogen receptors with the neurotrophins and their receptors in the developing forebrain and (b) differential and reciprocal regulation of estrogen and NGF receptor mRNAs by their ligands in adult sensory neurons and PC12 cells. Organotypic explant (slice) cultures of the developing rat forebrain will be used for the study. It will be tested whether interactions of estrogen and neurotrophins are required for both the development and survival of CNS target, as well as for the regulation of the estrogen and neurotrophin receptor genes. A combination of histological, molecular biological and biochemical techniques will be used to study gene transcription and neuronal differentiation and survival. Morphological findings will be correlated with functional output, using sensitive quantitative measures of estrogen binding, gene transcription and neurotrophin receptor content and function. The studies represent direct analysis of the distribution, molecular control, and functional responses of certain key elements involved in the interactions of estrogen and the neurotrophins [e.g. the neurons themselves and the estrogen and neurotrophin receptor systems].
