p21 Ras and phosphatidylinositol-3 kinase are required for survival of wild-type and NF1 mutant sensory neurons

Laura J. Klesse, Luis F. Parada

Research output: Contribution to journalArticle

107 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)10420-10428
Number of pages9
JournalJournal of Neuroscience
Volume18
Issue number24
DOIs
StatePublished - Dec 15 1998

Keywords

  • NGF
  • Neurotrophin signaling
  • PI 3 kinase
  • Recombinant adenovirus
  • Sensory neuron survival
  • p21 ras

ASJC Scopus subject areas

  • Neuroscience(all)

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