Inhibition of glycogen synthase kinase 3beta in sensory neurons in culture alters filopodia dynamics and microtubule distribution in growth cones.
MAP1B is a major microtubule-associated phospho-protein in growing axons and growth cones. Recent findings suggest that glycogen synthase kinase 3beta (GSK-3beta) phosphorylation of MAP1B may act as a molecular switch to regulate microtubule stability during axonogenesis. The effects of lithium, an inhibitor of GSK-3beta, on neurons in culture, are consistent with this suggestion. However, lithium is not a specific inhibitor of GSK-3beta. In the experiments reported here we have compared the effects of lithium with SB-216763, a new, potent and specific inhibitor of GSK-3 that has a different mechanism of action from lithium. We examined the effects of inhibition of GSK-3beta on axonogenesis, microtubule distribution, and growth cone behavior in cultured embryonic chick primary sensory neurons. Both compounds reduced axon elongation rates and increased growth cone size. In addition, both compounds slowed growth cone filopodia dynamics. These behavioral changes correlated with a decrease in MAP1B phosphorylation and an increase in the number of stable microtubules in growth cones. These results suggest that a major role of MAP1B in growing axons and growth cones is to regulate microtubule and actin filament stability. Furthermore, this function is regulated by phosphorylation of MAP1B by GSK-3beta.
Owen
Rebecca
R
The MRC Centre for Developmental Neurobiology, King's College London, Room 4.26B, New Hunts House, Guy's Campus, London SE1 1UL, UK.
Gordon-Weeks
Phillip R
PR
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002642:Chick Embryo; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000196:embryology / Q000201:enzymology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D020439:Growth Cones / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D007211:Indoles / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D009475:Neurons, Afferent / Q000166:cytology / Q000201:enzymology*; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D011554:Pseudopodia / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D008869:Microtubule-Associated Proteins; C417521:SB 216763; C085284:microtubule-associated protein 1B; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3