Neurofibromin negatively regulates neurotrophin signaling through p21ras in embryonic sensory neurons.
Embryonic sensory and sympathetic neurons that lack neurofibromin, the protein product of the neurofibromatosis type 1 (Nfl) gene, survive and extend neurites in the absence of neurotrophins. To determine whether neurofibromin negatively regulates neurotrophin signaling through its interaction with p21ras, we used Fab antibody fragments to block Ras function in DRG, trigeminal, nodose, and SCG neurons isolated from Nfl(-/-) and wild-type mouse embryos. We show that introduction of anti-Ras Fab fragments significantly reduces the ability of neurofibromin-deficient neurons to survive in the absence of neurotrophins. Moreover, addition of H-ras protein enhances the survival of Nfl(-/-), but not wild-type, DRG neurons. Our results are consistent with a major role for neurofibromin in modulating Trk signaling through p21ras during neuronal development.
Vogel
K S
KS
Center for Developmental Biology, University of Texas Southwestern Medical Center, Dallas 75235-9133, USA. kvogel@lsumc.edu
El-Afandi
M
M
Parada
L F
LF
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D005333:Fetus / Q000166:cytology; D005727:Ganglia, Spinal / Q000166:cytology / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D006639:Histidine / Q000235:genetics; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D051379:Mice; D009414:Nerve Growth Factors / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D025542:Neurofibromin 1; D009475:Neurons, Afferent / Q000737:chemistry / Q000166:cytology / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020917:Receptor, trkA / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D007140:Immunoglobulin Fab Fragments; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D025542:Neurofibromin 1; D006639:Histidine; D020917:Receptor, trkA; D016283:Proto-Oncogene Proteins p21(ras)