During development, neurons become dependent on target-derived neurotrophins for survival and maintenance of differentiated functions. Failed or inappropriate target interactions in vivo, or withdrawal of neurotrophins in vitro, lead to a characteristic sequence of molecular cell death events termed apoptosis, The purpose of the proposed research is to examine the roles of the Nf1 gene product, neurofibromin, in modulating the apoptotic response to neurotrophin withdrawal, as well as the survival response to depolarization. Previously, we demonstrated that many sensory neurons isolated from Nf1-/- mouse embryos survive in the absence of neurotrophins. The scope of the experiments proposed for Year 1 included 1) comparison of the response of embryonic mouse sensory neurons to nerve growth factor withdrawal and subsequent rescue with depolarizing levels of KCl, 2) analysis of the roles of downstream signaling molecules (P13 kinase, MAP kinase) in regulating the survival response to depolarization, and 3) analysis of the response of neurofibromin-deficient sensory neurons to neurotrophin withdrawal. In the first year of funding, we have demonstrated that Nfl haploinsufficient DRG neurons differ in their responses to NGF withdrawal and depolarization- mediated rescue. In addition, we found that loss of neurofibromin does not protect all sensory neurons from apoptosis following NGF removal.