GSK3 beta regulates myelin-dependent axon outgrowth inhibition through CRMP4.
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.
Alabed
Yazan Z
YZ
Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada.
Pool
Madeline
M
Ong Tone
Stephan
S
Sutherland
Calum
C
Fournier
Alyson E
AE
D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D009185:Myelin Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; C449760:Dpysl3 protein, rat; D007211:Indoles; D008301:Maleimides; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; C417521:SB 216763; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
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