The long-term objective of our research is to elucidate the mechanism of action of neuronal growth factors that control development of the nervous system and survival of adult neurons. A family of neurotrophic growth factors, the neurotrophins, regulates the development of several classes of neurons and the maintenance of their differentiated state. Nerve growth factor (NGF) is the prototypical target derived neurotrophic growth factor. In addition to its prominent role during neurodevelopment, NGF can promote growth and survival of populations of adult neurons, including septal cholinergic neurons that normally degenerate in patients with Alzheimer's disease. Our work focuses on the mechanisms by which neurotrophin signaling is propagated from distal axons to neuronal nuclei to control the expression of genes that support growth and survival of neurons. We have shown that a retrogradely propagated NGF/TrkA signal in sympathetic neurons supports CREB activity, gene expression and neuronal survival. We also discovered that CREB family transcription factors are critical for growth and survival of neurons. Our more recent findings have shown that CREB activity is controlled not only by phosphorylation on its critical regulatory site, Ser133, but also by a novel neurotrophin-dependent signaling mechanism that governs CREB's DNA binding activity. Lastly, our recent findings indicate that the ubiquitous transcription factor, SRF (Serum Response Factor), appears to cooperate with CREB family members to support neurotrophin dependent gene expression. Thus, as part of our long-term goal of understanding how neurotrophins regulate the expression of genes that contribute to growth and survival of neurons, we propose: To establish how neurotrophin signals are differentially propagated retrogradely in developing neurons; To determine the function(s) and novel modes of regulation of CREB family transcription factors during neurotrophin signaling, and; To establish the role(s) of SRF-mediated gene expression during neurotrophin signaling to the nucleus. Results of the proposed experiments should provide critical insights into how neurotrophic growth factors support growth and survival of neurons during development and in adulthood. ? ?
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