CREB is a mediator of NGF-dependent gene expression, growth and survival of sympathetic neurons

Nerve growth factor (NGF) and other neurotrophins support survival and promote growth of neurons during development. Neurotrophins, like other extracellular stimuli, activate intracellular signals that are relayed to the nucleus to activate transcription factors and gene expression in neurons. However, the mechanisms by which NGF regulates gene expression remain unclear. Moreover, the contribution of NGF-dependent gene transcription to growth and survival of neurons is not known. My work has addressed the role of cAMP-response element (CRE)-binding proteins during neuronal signaling. The CRE is among the best-characterized cis-regulatory elements found in many stimulus induced genes. I have investigated the identity of proteins that bind to the CRE in neurons and the roles of these transcription factors during NGF signaling. CREB and ATF-2 were found to be the major CRE binding proteins in cortical neurons, sympathetic neurons and in many brain regions. In order to study the role of CREB in neurons, we generated and characterized a potent and specific inhibitor of CREB, A-CREB. Using this inhibitor, we found that CREB is a general mediator of stimulus-dependent expression of c-fos. We also found that CREB-mediated gene expression is both necessary and sufficient for NGF-promoted survival and growth of sympathetic neurons. NGF regulated expression of bcl-2, an anti-apoptotic gene, by a CREB-dependent mechanism in sympathetic neurons. In support of this idea, we found reduced amounts of Bcl-2 protein in extracts prepared from brains of CREB −/− mice compared to their littermates. Taken together, our data support a model in which neurotrophins function, in part, through a mechanism involving CREB-dependent expression of genes that promote neuronal growth and survival.