NGF-induced axon growth is mediated by localized inactivation of GSK-3beta and functions of the microtubule plus end binding protein APC.
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.
Zhou
Feng-Quan
FQ
UNC-Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Zhou
Jiang
J
Dedhar
Shoukat
S
Wu
Yao-Hong
YH
Snider
William D
WD
D011125:Adenomatous Polyposis Coli / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D049452:Green Fluorescent Proteins; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D008959:Models, Neurological; D016297:Mutagenesis, Site-Directed / Q000502:physiology; D009414:Nerve Growth Factors / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection / Q000379:methods; D014404:Tubulin / Q000378:metabolism; D051176:beta Catenin
D000970:Antineoplastic Agents; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; C405804:EB1 microtubule binding proteins; D004791:Enzyme Inhibitors; D008164:Luminescent Proteins; D008869:Microtubule-Associated Proteins; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014404:Tubulin; D051176:beta Catenin; D049452:Green Fluorescent Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3