GSK3-CRMP2 signaling mediates axonal regeneration induced by 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 knockin mice significantly compromised PTEN-mediated optic nerve regeneration as well as the activity of CRMP2, and to a lesser extent, mTOR. These GSK3 mediated negative effects on regeneration were rescued by viral expression of constitutively active CRMP2, despite decreased mTOR activation. 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.