Understanding the mechanisms underlying development of the nervous system is one of the fundamental goals of neurobiology. The adrenergic-cholinergic switch in sympathetic neurons represents a well-studied, physiologically relevant developmental model system in whiCh multiple enzyme and neuropeptide genes are coregulated by well Characterized differentiation factors. One such factor ciliary neurotrophic factor (CNTF) has been implicated in the determination of neuronal phenotype and survival, and more recently in the therapy of neurodegenerative disease. However, little Is known about the intracellular steps that mediate the effects of CNTF and related cytokines on gene expression. Recent findings of ours and others support the hypothesis that the ras protooncogene product plays an important role in the effects of these cytokines on neuronal differentiation. I propose to systematically test this hypothesis, initially by characterizing the requirement for Ras activation in the regulation of neuronal gene transcription by CNTF and the related cytokine differentiation factor, leukemia inhibitory factor (LlF). Next, we will dissect the components of this regulation by focusing on how CNTF and LIF activate Ras, and then on how Ras activation in turn leads to neuropeptide gene transcription in R neuroblastoma cell line. Finally, we will investigate whether Ras mediates cytokine effects in neuronal models of development and disease, including cultured sympathetic and nigral neurons.
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