| Autor: |
Leibinger M; Division of Experimental Neurology, Department of Neurology, Heinrich Heine University of Düsseldorf, 40225 Duesseldorf, Germany., Andreadaki A; Division of Experimental Neurology, Department of Neurology, Heinrich Heine University of Düsseldorf, 40225 Duesseldorf, Germany., Golla R; Division of Experimental Neurology, Department of Neurology, Heinrich Heine University of Düsseldorf, 40225 Duesseldorf, Germany., Levin E; Division of Experimental Neurology, Department of Neurology, Heinrich Heine University of Düsseldorf, 40225 Duesseldorf, Germany., Hilla AM; Division of Experimental Neurology, Department of Neurology, Heinrich Heine University of Düsseldorf, 40225 Duesseldorf, Germany., Diekmann H; Division of Experimental Neurology, Department of Neurology, Heinrich Heine University of Düsseldorf, 40225 Duesseldorf, Germany., Fischer D; Division of Experimental Neurology, Department of Neurology, Heinrich Heine University of Düsseldorf, 40225 Duesseldorf, Germany dietmar.fischer@uni-duesseldorf.de. |
| Abstrakt: |
Implications of GSK3 activity for axon regeneration are often inconsistent, if not controversial. Sustained GSK3 activity in GSK3 S/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 (CRMP2 T/A ). These results underscore the prevalent requirement of active CRMP2 for optic nerve regeneration. Strikingly, expression of CRMP2 T/A in GSK3 S/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. |
