Abstract
AbstractKnockout of phosphatase and tensin homolog (PTEN‐/‐) is neuroprotective and promotes axon regeneration in mature neurons. Elevation and maintenance of mTOR activity in injured neurons have been proposed as the main 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 GSK3S/A knockin mice significantly compromised PTEN‐/‐‐mediated optic nerve regeneration as well as the activity of CRMP2, and to a lesser extent, mTOR. These GSK3S/A mediated negative effects on regeneration were rescued by viral expression of constitutively active CRMP2T/A, despite decreased mTOR activation. GSK3S/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
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