Neurofibromin and Neuronal Apoptosis
Annual summary rept. 1 Jul 2003-30 Jun 2004
TEXAS UNIV HEALTH SCIENCE CENTER AT SANANTONIO
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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 for Year 2 included 1 assessing synergy between the survival-promoting effects of neurotrophins and activity-mediated signaling, 2 characterizing the apoptotic response to ceramide, 3 identifying signaling components that mediate depolarization rescue, and 4 incorporating sympathetic neurons into the analyses of Nf1-deficiency and responses to neurotrophin withdrawal. Our results indicate that Nf1-- sensory and sympathetic neurons differ in their resistance to apoptosis initiated by NGF withdrawal, and propose that the timing of target contact may in part account for these differences. In addition, we have confirmed that Nf1 haploinsufficiency increases resistance to apoptosis and sensitivity to rescue by depolarization for both sensory and sympathetic neurons.
- Anatomy and Physiology
- Medicine and Medical Research