The brain is a major target of estrogen throughout life. My laboratory was the first to discover that estrogen enhances the growth and differentiation of axons and dendrites (neurites) in cultured slices of the developing forebrain and that estrogen and neurotrophin receptors co-localize in developing forebrain neurons. This proposal addresses the intracellular pathways estrogen may use in mediating its growth-or neurite-promoting signals to the nucleus. The hypothesis underlying this proposal is that the estrogen receptor (ER) in the developing brain may be more than a ligand-induced transcriptional enhancer and may also act as a receptor with tyrosine kinase activity. When the ER is co- expressed with neural growth factor receptors, such as the neurotrophin (trk) receptors, this association may lead to the sharing of similar, if not overlapping, sequences of intracellular biochemical events. Cross-coupling of converging estrogen and neurotrophin signaling pathways may lead to the same nuclear end-points and regulation of the very same genes. We will use both organotypic explants (slices) of developing postnatal rat forebrain and neuronal (PC12 and PC12-E2) and non-neuronal (MCF-7; CHO-K1) tumour cell lines, as model culture systems. Cultures will be analyzed correlatively by a variety of biochemical, histological and immunological techniques. The experiments are designed to identify and characterize (I) neurotrophin signaling proteins activated by estrogen; (ii) the pathways or points of convergence shared by estrogen and the neurotrophins; (iii) aspects related to the nature of the receptors involved in mediating these actions; and (iv) the functional consequences of cross coupling of estrogen and neurotrophin signaling pathways for ER expression and neurite growth and differentiation. These studies investigate and entirely new and exciting area heretofore unexplored in the brain and have broad implications for estrogen actions throughout life Alzheimer s disease and for aging. Our earlier studies have already provided a physiological rationale for the use of estrogen as a prophylactic treatment to prevent or retard the cognitive disorders associated with these conditions. Characterizing estrogen signaling pathways that may or may not be brain-specific could lead to the synthesis of estrogen- like drugs, which could duplicate estrogen's positive attributes for the brain, while eliminating many of its undesirable peripheral effects on non-neural tissues.
| MacLusky, N J; Chalmers-Redman, R; Kay, G et al. (2003) Ovarian steroids reduce apoptosis induced by trophic insufficiency in nerve growth factor-differentiated PC12 cells and axotomized rat facial motoneurons. Neuroscience 118:741-54 |
