Neurofibromin and Neuronal Apoptosis

摘要

Our purpose is to examine the role of neurofibromin in modulating the survival of embryonic sensory and sympathetic neurons. To understand how reduced neurofibromin levels might impact the survival responses to activity- mediated signaling (mimicked with KCl) and to neurotrophins, we used dissociated cultures of Nf1+/- and exon23a-/- sensory and sympathetic neurons in an NGF withdrawal paradigm. Reduction or elimination of neurofibromin through targeted mutation leads to a diminished apoptotic response when NGF is removed, and also results in an improved response to activity-mediated survival signaling. Thus, Nf1-deficient neurons may be more sensitive to signaling interactions in the developing nervous system, and may be more resistant to environmental insults (low levels of survival factors, hypoxia, DNA damage) that promote apoptotic death. To begin to address possible mechanisms of enhanced survival in Nf1-deficient neurons, we are examining the contributions of Egln3 and SDHD to modulating apoptosis in precursors and neurons of the peripheral nervous system.