GSK3 roles, substrates and signalling in immature nerve terminals. (a) Inhibition of GSK3 activity is essential for the establishment of axonal polarity. GSK3 activity is inhibited by growth factors that signal through the PI3K/Akt signal transduction cascade. When GSK3 is active, it phosphorylates both CRMP-2 and APC, which prevents their interaction with microtubules, arresting microtubule polymerization. When GSK3 is inhibited by growth factors, it cannot phosphorylate CRMP-2 or APC; therefore microtubule polymerization is stimulated. (b) Axonal remodelling describes decreased axonal growth, increased axon diameter, and increased growth cone size when a nascent axon meets a postsynaptic target. Inhibition of GSK3 increases microtubule stability to allow axonal remodelling. GSK3 activity is inhibited by a divergent Wnt signalling cascade. When GSK3 is active, it phosphorylates MAP-1B; which results in increased microtubule instability. When GSK3 is inhibited by Wnts, it cannot phosphorylate MAP-1B therefore microtubules are stabilised.
