Both the Establishment and the Maintenance of Neuronal Polarity Require Active Mechanisms: Critical Roles of GSK-3(beta) 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-3(beta) activity in the axon versus the dendrites. A constitutively active GSK-3(beta) mutant inhibited axon formation, whereas multiple axons formed from a single neuron when GSK-3(beta) 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-3(beta) in determining neuronal polarity. Our results demonstrate that there are active mechanisms for maintaining as well as establishing neuronal polarity, indicate that GSK-3(beta) relays signaling from Akt and PTEN to play critical roles in neuronal polarity, and suggest that application of GSK-3(beta) inhibitors can be a novel approach to promote generation of new axons after neural injuries.