NGF-induced axon growth is mediated by localized inactivation of GSK-3beta and functions of the microtubule plus end binding protein APC

Neuron. 2004 Jun 24;42(6):897-912. doi: 10.1016/j.neuron.2004.05.011.

Abstract

Little is known about how nerve growth factor (NGF) signaling controls the regulated assembly of microtubules that underlies axon growth. Here we demonstrate that a tightly regulated and localized activation of phosphatidylinositol 3-kinase (PI3K) at the growth cone is essential for rapid axon growth induced by NGF. This spatially activated PI3K signaling is conveyed downstream through a localized inactivation of glycogen synthase kinase 3beta (GSK-3beta). These two spatially coupled kinases control axon growth via regulation of a microtubule plus end binding protein, adenomatous polyposis coli (APC). Our results demonstrate that NGF signals are transduced to the axon cytoskeleton via activation of a conserved cell polarity signaling pathway.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenomatous Polyposis Coli / metabolism*
  • Analysis of Variance
  • Animals
  • Antineoplastic Agents / pharmacology
  • Axons / drug effects
  • Axons / physiology*
  • Blotting, Western / methods
  • Cell Count
  • Cells, Cultured
  • Cytoskeletal Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Embryo, Mammalian
  • Enzyme Inhibitors / pharmacology
  • Fluorescent Antibody Technique / methods
  • Ganglia, Spinal / cytology
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Green Fluorescent Proteins
  • Growth Cones / drug effects
  • Growth Cones / physiology
  • Luminescent Proteins / metabolism
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Microtubules / metabolism*
  • Models, Neurological
  • Mutagenesis, Site-Directed / physiology
  • Nerve Growth Factors / immunology
  • Nerve Growth Factors / pharmacology
  • Nerve Growth Factors / physiology*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Trans-Activators / metabolism
  • Transfection / methods
  • Tubulin / metabolism
  • beta Catenin

Substances

  • Antineoplastic Agents
  • CTNNB1 protein, mouse
  • Cytoskeletal Proteins
  • EB1 microtubule binding proteins
  • Enzyme Inhibitors
  • Luminescent Proteins
  • Microtubule-Associated Proteins
  • Nerve Growth Factors
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Tubulin
  • beta Catenin
  • Green Fluorescent Proteins
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3