Myelin-associated inhibitors regulate cofilin phosphorylation and neuronal inhibition through LIM kinase and Slingshot phosphatase.
Myelin-associated inhibitors (MAIs) signal through a tripartate receptor complex on neurons to limit axon regeneration in the CNS. Inhibitory influences ultimately converge on the cytoskeleton to mediate growth cone collapse and neurite outgrowth inhibition. Rho GTPase and its downstream effector Rho kinase are key signaling intermediates in response to MAIs; however, the links between Rho and the actin cytoskeleton have not been fully defined. We found that Nogo-66, a potent inhibitory fragment of Nogo-A, signals through LIM (LIM is an acronym of the three gene products Lin-11, Isl-1, and Mec-3) kinase and Slingshot (SSH) phosphatase to regulate the phosphorylation profile of the actin depolymerization factor cofilin. Blockade of LIMK1 activation and subsequent cofilin phosphorylation circumvents myelin-dependent inhibition in chick dorsal root ganglion neurons, suggesting that phosphorylation and inactivation of cofilin is critical for neuronal inhibitory responses. Subsequent activation of SSH1 phosphatase mediates cofilin dephosphorylation and reactivation. Overexpression of SSH1 does not mimic the neurite outgrowth inhibitory effects of myelin, suggesting an alternative role in MAI inhibition. We speculate that SSH-mediated persistent cofilin activation may be responsible for maintaining an inhibited neuronal phenotype in response to myelin inhibitors.
Hsieh
Sidney H-K
SH
Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec, H3A 2B4, Canada.
Ferraro
Gino B
GB
Fournier
Alyson E
AE
D051339:Actin Depolymerizing Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D054461:Lim Kinases; D009185:Myelin Proteins / Q000378:metabolism / Q000502:physiology; D018992:Myelin-Associated Glycoprotein / Q000502:physiology*; D009433:Neural Inhibition / Q000502:physiology*; D000070798:Nogo Proteins; D016716:PC12 Cells; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology*; D051381:Rats
D051339:Actin Depolymerizing Factors; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D000070798:Nogo Proteins; C000603199:RTN4 protein, human; C000603197:Rtn4 protein, rat; D011494:Protein Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515894:Limk1 protein, rat; D010749:Phosphoprotein Phosphatases; C484329:SSH1 protein, human