Boosting CNS axon regeneration by harnessing antagonistic effects of GSK3 activity

• Published in: Proceedings of the National Academy of Sciences - PNAS 2017-07, Vol.114 (27), p.E5454-E5463
• Main Authors: Leibinger, Marco, Andreadaki, Anastasia, Golla, Renate, Levin, Evgeny, Hilla, Alexander M., Diekmann, Heike, Fischer, Dietmar
• Format: Article
• Language: English
• Subjects: Animals; Axons; Axons - physiology; Biological Sciences; Central nervous system; Central Nervous System - physiology; Female; Glycogen Synthase Kinase 3 - physiology; Inhibition; Intercellular Signaling Peptides and Proteins - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microtubule-associated protein 1; Microtubule-Associated Proteins - physiology; Myelin; Myelin Sheath - physiology; Nerve Regeneration; Nerve Tissue Proteins - physiology; Neurology; Optic chiasm; Optic nerve; Optic Nerve - physiology; Peripheral nerves; Peripheral Nervous System - physiology; Phosphorylation; PNAS Plus; Promotion; Regeneration; Retina; Retina - physiology; Retinal ganglion cells; Retinal Ganglion Cells - physiology; Rodents; Sciatic Nerve - physiology; Substrates
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1621225114

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.