Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators.
Axon-dendrite polarity is a cardinal feature of neuronal morphology essential for information flow. Here we report a differential distribution of GSK-3beta activity in the axon versus the dendrites. A constitutively active GSK-3beta mutant inhibited axon formation, whereas multiple axons formed from a single neuron when GSK-3beta activity was reduced by pharmacological inhibitors, a peptide inhibitor, or siRNAs. An active mechanism for maintaining neuronal polarity was revealed by the conversion of preexisting dendrites into axons upon GSK-3 inhibition. Biochemical and functional data show that the Akt kinase and the PTEN phosphatase are upstream of GSK-3beta in determining neuronal polarity. Our results demonstrate that there are active mechanisms for maintaining as well as establishing neuronal polarity, indicate that GSK-3beta relays signaling from Akt and PTEN to play critical roles in neuronal polarity, and suggest that application of GSK-3beta inhibitors can be a novel approach to promote generation of new axons after neural injuries.
Jiang
Hui
H
Institute of Neuroscience, Shanghai Institutes of Biological Sciences, The Graduate School, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Guo
Wei
W
Liang
Xinhua
X
Rao
Yi
Y
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology*; D002478:Cells, Cultured; D003712:Dendrites / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology; D009154:Mutation; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats
D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C494920:Akt1 protein, rat; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat