Implications of GSK3 activity for axon regeneration are often inconsistent, if not controversial. Sustained GSK3 activity in GSK3S/A knock-in mice reportedly accelerates peripheral nerve regeneration via increased MAP1B phosphorylation and concomitantly reduces microtubule detyrosination. In contrast, the current study shows that lens injury-stimulated optic nerve regeneration was significantly compromised in these knock-in mice. Phosphorylation of MAP1B and CRMP2 was expectedly increased in retinal ganglion cell (RGC) axons upon enhanced GSK3 activity, but, surprisingly, no GSK3-mediated CRMP2 inhibition was detected in sciatic nerves, thus revealing a fundamental difference between central and peripheral axons. Conversely, genetic or shRNA-mediated conditional KO/knockdown of GSK3β reduced inhibitory phosphorylation of CRMP2 in RGCs and improved optic nerve regeneration. Accordingly, GSK3β KO-mediated neurite growth promotion and myelin disinhibition were abrogated by CRMP2 inhibition and largely mimicked in WT neurons upon expression of constitutively active CRMP2 (CRMP2T/A). These results underscore the prevalent requirement of active CRMP2 for optic nerve regeneration. Strikingly, expression of CRMP2T/A in GSK3S/A RGCs further boosted optic nerve regeneration, with axons reaching the optic chiasm within 3 wk. Thus, active GSK3 can also markedly promote axonal growth in central nerves if CRMP2 concurrently remains active. Similar to peripheral nerves, GSK3-mediated MAP1B phosphorylation/activation and the reduction of microtubule detyrosination contributed to this effect. Overall, these findings reconcile conflicting data on GSK3-mediated axon regeneration. In addition, the concept of complementary modulation of normally antagonistically targeted GSK3 substrates offers a therapeutically applicable approach to potentiate the regenerative outcome in the injured CNS.
Pubmed ID: 28630333 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This monoclonal targets Neuronal Class III beta-Tubulin (TUJ1) Purified
View all literature mentionsThis polyclonal targets CRMP2 (phospho T514)
View all literature mentionsThis polyclonal targets Dpysl2
View all literature mentionsThis monoclonal targets Gsk3b
View all literature mentionsThis monoclonal targets GSK-3 beta
View all literature mentionsThis unknown targets Tubulin, Detyrosinated
View all literature mentionsThis unknown targets Phospho-MAP1B (Thr1265)
View all literature mentionsThis monoclonal targets 200 kD Neurofilament Heavy
View all literature mentionsThis polyclonal targets GSK3 alpha (Phospho Ser21)
View all literature mentionsThis monoclonal targets Gsk3a
View all literature mentionsThis unknown targets HA
View all literature mentionsThis monoclonal targets
View all literature mentionsThis polyclonal targets Gsk3a
View all literature mentionsThis polyclonal targets Dpysl2
View all literature mentionsThis polyclonal targets CRMP2 (phospho T514)
View all literature mentionsThis monoclonal targets Neuronal Class III beta-Tubulin (TUJ1) Purified
View all literature mentionsThis monoclonal targets Gsk3b
View all literature mentions