Although maintaining the integrity of the central nervous system (CNS) is of extreme importance to human health and function, relatively little is known about the signaling processes involved in the proliferation, differentiation and survival of CNS neurons. Two growth factors, epidermal growth factor (EGF) and fibroblast-derived growth factor (FGF), have been implicated as mitogens, differentiating agents, and neurotrophic agents for neuronal stem cells and neurons in a number of CNS regions, including the hippocampus. The hippocampal-septal axis plays a key role in learning and memory, is involved in many neuropathies including Alzheimer's disease, epilepsy and stroke, and has a relative structural simplicity which has proven useful in studies of development and plasticity. In order to investigate the mechanism by which growth factors influence hippocampal development and function, we have generated neuronal cell lines of hippocampal lineage that proliferate in response to EGF and differentiate into a nonproliferating, neuronal phenotype in response to bFGF. In the present proposal, we will focus on the mechanism by which growth factors differentiate neuronal cells. We propose to use these cell lines to define major signalling intermediates in the bFGF signal transduction pathways and test the hypothesis that these intermediates are responsible for the actions of bFGF as a differentiating agent/ Specifically, we plan to identify activated intermediates in the FGF signal transduction pathway, determine the role of activated intermediates in the FGF signaling pathway, and identify and characterize genes that may code for novel intermediates in the signaling pathways leading to differentiation of H19-7 cells. The results of these studies will define key signaling intermediates that influence neuronal differentiation and increase our understanding of the processes that lead to neoplastic transformation and neurodegenerative disease involving neuronal differentiation and survival.
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