The longterm 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. The development of several classes of neurons, and the maintenance of their differentiated state, are regulated by a family of neurotrophic growth factors, the neurotrophins. Nerve growth factor (NGF) is the prototypical target-derived neurotrophic growth factor. In addition to its prominent role during neurodevelopment, NGF can promote survival of populations of adult neurons, including septal cholinergic neurons that normally die in patients with Alzheimer's disease. Our work focuses on the mechanisms by which neurotrophins regulate expression of genes that contribute to growth, differentiation and survival of neurons. Neurotrophins activate the transcription factor CREB (cAMP-response element binding protein) by inducing phosphorylation of CREB on a transcriptional regulatory site, Ser-133. This phosphorylation event is catalyzed by RSK2, a growth factor-sensitive protein kinase. In addition, phosphorylation of CREB Ser-133 is regulated by a retrogradely propagated neurotrophin signal in neonatal sympathetic neurons. Lastly, preliminary results indicate that CREB, or a closely related CREB family member, is critical for NGF induction of transcription of c-fos. Since many, if not most, NGF-sensitive genes contain CREB binding sites within their upstream regulatory regions, it is likely that CREB and CREB family members are critical mediators of the general nuclear response to target-derived NGF. As part of an overall goal to understand NGF regulation of expression of genes that contribute to neuronal differentiation, plasticity and survival, the specific aims of the present proposal are: 1) To characterize the mechanisms of retrograde NGF signaling to transcription factor CREB and other nuclear targets in developing sympathetic neurons; 2) To determine the functional consequences of retrograde NGF signaling to CREB and other nuclear targets, and 3) To establish the requirement of CREB and CREB family members in NGF signal transaction. Together, the proposed research will provide insight into the mechanism of NGF signal transduction, the molecular basis of neurodevelopment, and the control of survival of adult neurons, which are susceptible to death in debilitating neurodegenerative diseases.
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