MECHANISMS OF ESTROGEN ACTION IN THE DEVELOPING CNS

This is a renewal of an ADAMHA Research Scientist Award. The long-term goal of the research program is to determine how the gonadal steroid hormone estrogen and members of the neurotrophin family of peptide growth factors [e.g., nerve growth factor (NGF); brain derived neurotrophic factor (BDNF); neurotrophin-3 (NT-3)] collaborate in the differentiation and survival of CNS target neurons. This proposal tests the hypothesis that interactions of estrogen and the neurotrophins [e.g., nerve growth factor (NGF); brain derived neurotrophic factor (BDNF); neurotrophin-3 (NT-3)] are essential for regulation of the estrogen and neurotrophin (p75 and trk family) receptor genes and for estrogen signaling pathways. The proposed experiments address two major issues raised by our observations of co-localization of estrogen and neurotrophin receptors in developing CNS neurons; namely, (l) the potential for reciprocal regulation of the estrogen and neurotrophin receptor genes by their ligands; and (ii) the signaling pathways that may be involved in estrogen actions and in its interactions with the neurotrophins. Organotypic (slice) cultures from two estrogen and neurotrophin target regions of developing rat brain, the cerebral cortex and septum/diagonal band, will be used. This is a novel system the development of which the P.I. contributed to and used at length to characterize the actions of estrogen in the developing brain. The cultures will be analyzed by histological, molecular biological and biochemical techniques to study regulation of gene expression. Morphological findings will be correlated with functional output, using sensitive quantitative measures of estrogen binding and estrogen receptor content, neurotrophin receptor content and function, and protein tyrosine phosphorylation. The experiments represent aspects related to direct qualitative and quantitative analyses of the molecular control and functional responses of certain key elements involved in estrogen/neurotrophin interactions [e.g., the estrogen and neurotrophin receptor systems, and some target proteins and genes]. The proposed studies extend the knowledge gained from peripheral neurons to the developing CNS and provide an understanding of how synaptic interconnections may regulate and modify the basic molecular responses of the simpler peripheral models to these ligands. The proposed studies address an entirely new and very exciting area concerning reciprocal interactions of estrogen and the neurotrophins as very important regulatory influences on neuronal development, survival, plasticity and repair in brain regions that underlie learning, memory and other cognitive functions. These experiments have significance for understanding the mechanisms underlying the genesis of a wide variety of human abnormalities of considerable importance which include: the sexually dimorphic childhood disorders of cognition (learning disabilities), infantile autism, delayed speech acquisition, and stuttering; the cognitive deficits associated with Turner's syndrome, aging and Alzheimer's disease and perhaps even schizophrenia and may provide clues for developing therapeutic approaches to some of them. These studies will continue to lead to new fields, requiring new knowledge and new methodologies, which, along with the learning opportunities, afforded by the several collaborative associations, will greatly benefit and continue to significantly advance professional growth.