Abstract:

GSK3 phosphorylation reportedly supports regeneration-promoting gene transcription (e.g., SMAD expression). Therefore, opposing GSK3 regulation in different neuronal compartments (e.g., soma vs. growth cone) or direct manipulation of downstream GSK3 targets instead of GSK3 itself may further increase the regenerative response in comparison to globally increased GSK3 activity. Finally, it needs to be investigated whether GSK3 DKI mice show improved axon regeneration also in the CNS. We envisage that increased microtubule dynamics might be rather unfavorable for regenerating axons that encounter an inhibitory (thus microtubule-depolymerizing) environment as in the CNS. Therefore, negligible or even opposite effects of GSK3S/A on CNS axonal regeneration are equally expectable and further experiments are required to address these possibilities. Surely, the complexity of GSK3 signaling will provide more interesting features in the future, which could then potentially be developed into novel therapeutic treatment options for nerve injuries.