Involvement of ras p21 in neurotrophin-induced response of sensory, but not sympathetic neurons.
Little is known about the signal transduction mechanisms involved in the response to neurotrophins and other neurotrophic factors in neurons, beyond the activation of the tyrosine kinase activity of the neurotrophin receptors belonging to the trk family. We have previously shown that the introduction of the oncogene product ras p21 into the cytoplasm of chick embryonic neurons can reproduce the survival and neurite-outgrowth promoting effects of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and of ciliary neurotrophic factor (CNTF). To assess the potential signal-transducing role of endogenous ras p21, we introduced function-blocking anti-ras antibodies or their Fab fragments into cultured chick embryonic neurons. The BDNF-induced neurite outgrowth in E12 nodose ganglion neurons was reduced to below control levels, and the NGF-induced survival of E9 dorsal root ganglion (DRG) neurons was inhibited in a specific and dose-dependent fashion. Both effects could be reversed by saturating the epitope-binding sites with biologically inactive ras p21 before microinjection. Surprisingly, ras p21 did not promote the survival of NGF-dependent E12 chick sympathetic neurons, and the NGF-induced survival in these cells was not inhibited by the Fab-fragments. The survival effect of CNTF on ras-responsive ciliary neurons could not be blocked by anti-ras Fab fragments. These results indicate an involvement of ras p21 in the signal transduction of neurotrophic factors in sensory, but not sympathetic or ciliary neurons, pointing to the existence of different signaling pathways not only in CNTF-responsive, but also in neurotrophin-responsive neuronal populations.
Borasio
G D
GD
Neurologische Klinik, Ludwig Maximilians Universität München, Klinikum Grosshadern, Germany.
Markus
A
A
Wittinghofer
A
A
Barde
Y A
YA
Heumann
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor; D002478:Cells, Cultured / Q000187:drug effects; D002642:Chick Embryo; D020934:Ciliary Neurotrophic Factor; D005728:Ganglia, Sympathetic / Q000502:physiology*; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D009475:Neurons, Afferent / Q000502:physiology*; D009620:Nodose Ganglion / Q000502:physiology*; D015689:Oncogene Protein p21(ras) / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D000911:Antibodies, Monoclonal; D019208:Brain-Derived Neurotrophic Factor; D020934:Ciliary Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D015689:Oncogene Protein p21(ras)