Neuronal polarity is regulated by glycogen synthase kinase-3 (GSK-3beta) independently of Akt/PKB serine phosphorylation.
An essential step during the development of hippocampal neurons is the polarised outgrowth of a single axon. Recently, it has been suggested that inhibition of glycogen synthase kinase-3beta (GSK-3beta) via Akt/PKB-dependent phosphorylation of Ser9, specifically at the tip of the presumptive axon, is required for selective axonal outgrowth. We now report that, by using neurons from double knock-in mice in which Ser9 and Ser21 of the two GSK-3beta isoforms have been replaced by Ala, polarity develops independently of phosphorylation at these sites. Nevertheless, global inhibition of GSK-3beta disturbs polarity development by leading to the formation of multiple axon-like processes in both control and knock-in neurons. This unpolarised outgrowth is accompanied by the symmetric delivery of membrane components to all neurites. Finally, the adenomatous polyposis coli (APC) protein accumulates at the tip of one neurite before and during axon elongation, but global inhibition of GSK-3beta leads to APC protein accumulation in all neurites. We conclude that GSK-3beta inhibition promotes the development of neuronal polarity, but that this is not mediated by Akt/PKB-dependent phosphorylation.
Gärtner
Annette
A
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UK. a.gaertner@ucl.ac.uk
Huang
Xu
X
Hall
Alan
A
D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D001369:Axons; D016764:Cell Polarity / Q000502:physiology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism / Q000502:physiology*; D006056:Golgi Apparatus / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D014018:Tissue Distribution; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism
D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3