Neurotrophin signaling and transcription factor regulation in the developing nervous system

Transcription factor regulation is a highly complex process. The cell has the difficult task of translating extracellular stimuli into specific gene expression programs using only a handful of common signaling molecules. In this way, the cell is able to respond to its external environment appropriately. Growth factors play a role in many aspects of neuronal development and function, including axon outgrowth, cell survival, and plasticity. These effects are, in large part, due to downstream gene transcription targets.; Two ubiquitous transcription factors, c-AMP Response Element Binding Factor (CREB) and Serum Response Factor (SRF), are both activated by growth factors. CREB plays a role in myriad neuronal functions, including cell survival and maintenance, and is activated by numerous upstream signaling cascades. CREB activation occurs through S133 phosphorylation, although other forms of regulation are likely to occur. SRF is also involved in many cellular processes, although it's role in neuronal function has not been well studied.; In our study, we have identified a novel form of CREB regulation downstream of growth factor signaling, involving nNOS-dependent CREB-DNA binding. BDNF/TrkB activation leads to an increase in NOS activity and inducible nitrosylation of factors at the CRE of several different genes. This nNOS pathway affecting CREB-DNA binding is separate and distinct from the pathway leading from BDNF/TrkB to CREB S133 phosphorylation.; The role of SRF in neuronal function has been difficult to study due to the lack of a viable Srf null animal. The generation of conditional Srf mutants has provided a tool to begin to study how SRF affects the nervous system. We looked at the effects of SRF-dependent trasnscription on DRG sensory neuron development. Srf mutants lack final target innervation and exhibit decreased axon branching, similar to the phenotype seen in NGF mutants. We also found that NGF induces SRE-mediated transcription, suggesting that in vivo, NGF and SRF are in a common pathway involved in sensory neuron development.