TY - JOUR
T1 - p21 Ras and phosphatidylinositol-3 kinase are required for survival of wild-type and NF1 mutant sensory neurons
AU - Klesse, Laura J.
AU - Parada, Luis F.
PY - 1998/12/15
Y1 - 1998/12/15
N2 - Nerve growth factor (NGF) is a required differentiation and survival factor for sympathetic and a majority of neural crest-derived sensory neurons in the developing vertebrate peripheral nervous system. Although much is known about the function of NGF, the intracellular signaling cascade that it uses continues to be a subject of intense study. p21 ras signaling is considered necessary for sensory neuron survival. How additional intermediates downstream or in parallel may function has not been fully understood yet. Two intracellular signaling cascades, extra cellular regulated kinase (erk) and phosphatidylinositol-3 (PI 3) kinase, transduce NGF signaling n the pheochromocytoma cell line PC12. To elucidate the role these cascades play in survival and differentiation, we used a combination of recombinant adenoviruses and chemical inhibitors to perturb these pathways in sensory neurons from wild-type mice and mice deficient for neurofibromin in which the survival and differentiation pathway is constitutively active. We demonstrate that ras activity is both necessary and sufficient for the survival of embryonic sensory neurons. Downstream of ras, however, the erk cascade is neither required nor sufficient for neuron survival or overall differentiation. Instead, the activity of PI 3 kinase is necessary for the survival of the wild-type and neurofibromin-deficient neurons. Therefore, we conclude that in sensory neurons, NGF acts via a signaling pathway, which includes both ras and PI 3 kinase.
AB - Nerve growth factor (NGF) is a required differentiation and survival factor for sympathetic and a majority of neural crest-derived sensory neurons in the developing vertebrate peripheral nervous system. Although much is known about the function of NGF, the intracellular signaling cascade that it uses continues to be a subject of intense study. p21 ras signaling is considered necessary for sensory neuron survival. How additional intermediates downstream or in parallel may function has not been fully understood yet. Two intracellular signaling cascades, extra cellular regulated kinase (erk) and phosphatidylinositol-3 (PI 3) kinase, transduce NGF signaling n the pheochromocytoma cell line PC12. To elucidate the role these cascades play in survival and differentiation, we used a combination of recombinant adenoviruses and chemical inhibitors to perturb these pathways in sensory neurons from wild-type mice and mice deficient for neurofibromin in which the survival and differentiation pathway is constitutively active. We demonstrate that ras activity is both necessary and sufficient for the survival of embryonic sensory neurons. Downstream of ras, however, the erk cascade is neither required nor sufficient for neuron survival or overall differentiation. Instead, the activity of PI 3 kinase is necessary for the survival of the wild-type and neurofibromin-deficient neurons. Therefore, we conclude that in sensory neurons, NGF acts via a signaling pathway, which includes both ras and PI 3 kinase.
KW - NGF
KW - Neurotrophin signaling
KW - PI 3 kinase
KW - Recombinant adenovirus
KW - Sensory neuron survival
KW - p21 ras
UR - http://www.scopus.com/inward/record.url?scp=0032535276&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032535276&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.18-24-10420.1998
DO - 10.1523/jneurosci.18-24-10420.1998
M3 - Article
C2 - 9852579
AN - SCOPUS:0032535276
SN - 0270-6474
VL - 18
SP - 10420
EP - 10428
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 24
ER -