Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons.
Mutations at the neurofibromatosis 1 (NF1) locus in humans and mice result in abnormal growth of neural crest-derived cells, including melanocytes and Schwann cells. We have exploited a targeted disruption of the NF1 gene in mice to examine the role of neurofibromin in the acquisition of neurotrophin dependence in embryonic neurons. We show that both 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 unless nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) is added to the culture medium. Moreover, NF1 (-/-) sympathetic neurons 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 neurotrophin-mediated signaling for survival of embryonic peripheral neurons.
Vogel
K S
KS
Center for Developmental Biology, University of Texas Southwestern Medical Center, Dallas 75235-9133, USA.
Brannan
C I
CI
Jenkins
N A
NA
Copeland
N G
NG
Parada
L F
LF
D000818:Animals; D001369:Axons / Q000502:physiology; D002470:Cell Survival / Q000235:genetics; D005727:Ganglia, Spinal / Q000166:cytology / Q000502:physiology; D016514:Genes, Neurofibromatosis 1 / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation / Q000235:genetics; D009414:Nerve Growth Factors / Q000502:physiology*; D025542:Neurofibromin 1; D009475:Neurons, Afferent / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D011506:Proteins / Q000235:genetics*; D013564:Sympathetic Nervous System / Q000166:cytology / Q000196:embryology / Q000502:physiology*; D014278:Trigeminal Nuclei / Q000166:cytology
D009414:Nerve Growth Factors; D025542:Neurofibromin 1; D011506:Proteins