GSK3-CRMP2 signaling mediates axonal regeneration induced by Pten knockout

Knockout of phosphatase and tensin homolog (PTEN(−/−)) is neuroprotective and promotes axon regeneration in mature neurons. Elevation of mTOR activity in injured neurons has been proposed as the primary underlying mechanism. Here we demonstrate that PTEN(−/−) also abrogates the inhibitory activity of GSK3 on collapsin response mediator protein 2 (CRMP2) in retinal ganglion cell (RGC) axons. Moreover, maintenance of GSK3 activity in Gsk3(S/A) knockin mice significantly compromised PTEN(−/−)-mediated optic nerve regeneration as well as the activity of CRMP2, and to a lesser extent, mTOR. These GSK3(S/A) mediated negative effects on regeneration were rescued by viral expression of constitutively active CRMP2(T/A), despite decreased mTOR activation. Gsk3(S/A) knockin or CRMP2 inhibition also decreased PTEN(−/−) mediated neurite growth of RGCs in culture and disinhibition towards CNS myelin. Thus, the GSK3/CRMP2 pathway is essential for PTEN(−/−) mediated axon regeneration. These new mechanistic insights may help to find novel strategies to promote axon regeneration.