The neuron-specific isoform of glycogen synthase kinase-3beta is required for axon growth

J. Neurochem. (2010) 10.1111/j.1471-4159.2010.06581.x Abstract Glycogen synthase kinase-3 (GSK-3) has become an important target for the treatment of mood disorders and neurodegenerative disease. It comprises three enzymes, GSK-3α, β and the neuron-specific isoform, β2. GSK-3 regulates axon growth by phosphorylating microtubule-associated proteins including Tau. A genetic polymorphism that leads to an increase in the ratio of GSK-3β1 to GSK-3β2 interacts with Tau haplotypes to modify disease risk in Parkinson’s and Alzheimer’s disease. We have examined the roles of each isoform of GSK-3 in neurons. Silencing of GSK-3β2 inhibited retinoic acid-induced neurite outgrowth in SH-SY5Y neuroblastoma cells and axon growth in rat cortical neurons. Inhibition of neurite outgrowth was prevented by co-expression of GSK-3β2 but not by co-expression of GSK-3α or GSK-3β1. Ectopic expression GSK-3β2 enhanced the effects of retinoic acid on neurite length and induced neurite formation in the absence of retinoic acid. GSK-3β2 phosphorylated Tau at a subset of those sites phosphorylated by GSK-3β1. In addition, Axin, which regulates responses to Wnt signals, associated more readily with GSK-3β1 than with GSK-3β2. Our results suggest that GSK-3 inhibitors that target the Axin-binding site in GSK-3 will preserve the beneficial effects of GSK-3β2 on axon growth.