LOSS OF NEUROFIBROMIN RESULTS IN NEUROTROPHIN-INDEPENDENT SURVIVAL OFEMBRYONIC SENSORY AND SYMPATHETIC NEURONS

Mutations at the neurofibromatosis 1 (NF1) locus in humans and mice re sult in abnormal growth of neural crest-derived cells, including melan ocytes and Schwann cells. We have exploited a targeted disruption of t he NF1 gene in mice to examine the role of neurofibromin in the acquis ition of neurotrophin dependence in embryonic neurons. We show that bo th neural crest- and placode-derived sensory neurons isolated from NF1 (-/-) embryos develop, extend neurites, and survive in the absence of neurotrophins, whereas their wild-type counterparts die rapidly unles s nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF ) is added to the culture medium. Moreover, NF1 (-/-) sympathetic neur ons survive for extended periods and acquire mature morphology in the presence of NGF-blocking antibodies. Our results are consistent with a model wherein neurofibromin acts as a negative regulator of neurotrop hin-mediated signaling for survival of embryonic peripheral neurons.