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GSK3 beta regulates myelin-dependent axon outgrowth inhibition through CRMP4
Yazan Z Alabed1, Madeline Pool, Stephan Ong Tone
1Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada.
Abstract:
Myelin-associated inhibitors (MAIs) contribute to failed regeneration in the CNS. The intracellular signaling pathways through which MAIs block axonal repair remain largely unknown. Here, we report that the kinase GSK3beta is directly phosphorylated and inactivated by MAIs, consequently regulating protein-protein interactions that are critical for myelin-dependent inhibition. Inhibition of GSK3beta mimics the neurite outgrowth inhibitory effect of myelin. The inhibitory effects of GSK3beta inhibitors and myelin are not additive indicating that GSK3beta is a major effector of MAIs. Consistent with this, overexpression of GSK3beta attenuates myelin inhibition. MAI-dependent phosphorylation and inactivation of GSK3beta regulate phosphorylation of CRMP4, a cytosolic regulator of myelin inhibition, and its ability to complex with RhoA. Introduction of a CRMP4 antagonist attenuates the neurite outgrowth inhibitory properties of GSK3beta inhibitors. We describe the first example of GSK3beta inactivation in response to inhibitory ligands and link the neurite outgrowth inhibitory effects of GSK3beta inhibition directly to CRMP4. These findings raise the possibility that GSK3beta inhibition will not effectively promote long-distance CNS regeneration following trauma such as spinal cord injury.
Insights
Myelin-associated inhibitors (MAIs) inactivate the kinase GSK3beta, blocking central nervous system (CNS) axonal repair. This GSK3beta inactivation is a key mechanism underlying MAI-induced growth inhibition, impacting potential spinal cord injury treatments.
Area of Science:
- Neuroscience
- Cell Biology
- Regenerative Medicine
Background:
- Myelin-associated inhibitors (MAIs) impede axonal regeneration in the central nervous system (CNS).
- The specific intracellular signaling pathways targeted by MAIs are not fully understood.
- Understanding these pathways is crucial for developing strategies to promote CNS repair.
Purpose of the Study:
- To elucidate the intracellular signaling mechanisms by which MAIs inhibit axonal repair.
- To identify key molecular players involved in myelin-dependent growth inhibition.
- To evaluate the role of Glycogen Synthase Kinase 3 beta (GSK3beta) in mediating MAI effects.
Main Methods:
- Investigated the direct interaction and phosphorylation of GSK3beta by MAIs.
- Assessed the functional consequences of GSK3beta inhibition on neurite outgrowth.
- Examined the interplay between GSK3beta, CRMP4, and RhoA signaling.
- Utilized overexpression of GSK3beta and CRMP4 antagonists as experimental tools.
Main Results:
- MAIs directly phosphorylate and inactivate the kinase GSK3beta.
- Inhibition of GSK3beta effectively mimics the neurite outgrowth inhibitory effects of myelin.
- GSK3beta acts as a major effector of MAIs, as its inhibition and myelin effects are not additive.
- Overexpression of GSK3beta mitigates myelin-induced inhibition.
- MAI-induced GSK3beta inactivation modulates CRMP4 phosphorylation and its complex formation with RhoA.
Conclusions:
- GSK3beta inactivation is a novel mechanism by which MAIs inhibit axonal regeneration.
- GSK3beta inactivation directly links to CRMP4 regulation, mediating myelin's inhibitory effects.
- Targeting GSK3beta alone may not be sufficient for promoting long-distance CNS regeneration after injury, such as spinal cord injury.
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