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Inactivation of Rho signaling pathway promotes CNS axon regeneration
M Lehmann1, A Fournier, I Selles-Navarro
1Département de Pathologie et Biologie Cellulaire, Université de Montréal, Succursale Centreville, Montréal, Québec H3C 3J7, Canada.
Abstract:
Regeneration in the CNS is blocked by many different growth inhibitory proteins. To foster regeneration, we have investigated a strategy to block the neuronal response to growth inhibitory signals. Here, we report that injured axons regrow directly on complex inhibitory substrates when Rho GTPase is inactivated. Treatment of PC12 cells with C3 enzyme to inactivate Rho and transfection with dominant negative Rho allowed neurite growth on inhibitory substrates. Primary retinal neurons treated with C3 extended neurites on myelin-associated glycoprotein and myelin substrates. To explore regeneration in vivo, we crushed optic nerves of adult rat. After C3 treatment, numerous cut axons traversed the lesion to regrow in the distal white matter of the optic nerve. These results indicate that targeting signaling mechanisms converging to Rho stimulates axon regeneration on inhibitory CNS substrates.
Insights
Inactivating Rho GTPase enables injured central nervous system (CNS) axons to regrow on inhibitory substrates. This strategy promotes axon regeneration after optic nerve injury in rats.
Area of Science:
- Neuroscience
- Cell Biology
- Regenerative Medicine
Background:
- Central nervous system (CNS) regeneration is significantly hindered by growth inhibitory proteins present in the environment.
- Developing strategies to overcome these inhibitory signals is crucial for promoting CNS repair.
Purpose of the Study:
- To investigate the potential of blocking neuronal responses to growth inhibitory signals by targeting Rho GTPase.
- To determine if Rho GTPase inactivation can promote axon regeneration on complex inhibitory substrates in vitro and in vivo.
Main Methods:
- Inactivation of Rho GTPase in PC12 cells and primary retinal neurons using C3 enzyme or dominant-negative Rho.
- Assessment of neurite outgrowth on inhibitory substrates like myelin-associated glycoprotein and myelin.
- In vivo experiments involving crushing adult rat optic nerves followed by C3 treatment.
Main Results:
- PC12 cells and primary retinal neurons exhibited neurite growth on inhibitory substrates upon Rho GTPase inactivation.
- In vivo, C3 treatment facilitated the regeneration of crushed optic nerve axons across the lesion site into the distal white matter.
- Successful regeneration occurred directly on complex inhibitory CNS substrates.
Conclusions:
- Inactivating Rho GTPase is a viable strategy to overcome CNS growth inhibition.
- Targeting signaling pathways converging on Rho GTPase can stimulate axon regeneration in the CNS.
- This approach holds promise for therapeutic interventions aimed at CNS repair.