Collapsin Response Mediator Protein-2 (CRMP-2) is expressed at high levels in the developing nervous system and plays a critical role in axonal outgrowth by specifying axon/dendrite fate and establishing neuronal polarity. CRMP-2 enhances axon elongation and branching by binding to tubulin heterodimers to promote microtubule assembly . GSK-3? inactivates CRMP-2 by phosphorylating it at Thr514. CRMP-2 is primed following phosphorylation at Ser522 by CDK5 and at Thr518 by GSK-3?. Phosphorylation of CRMP-2, which decreases tubulin binding ability, can be inhibited by NT-3 and BDNF through the PI3 kinase/Akt pathway. CRMP-2 also mediates semaphorin-induced growth cone collapse. Hyperphosphorylation of CRMP-2 is found in Alzheimer disease plaques with concurrent elevated GSK-3? activity in these patients.