Inhibition of GSK-3beta leading to the loss of phosphorylated MAP-1B is an early event in axonal remodelling induced by WNT-7a or lithium.
WNT-7a induces axonal spreading and branching in developing cerebellar granule neurons. This effect is mediated through the inhibition of GSK-3beta, a serine/threonine kinase and a component of the WNT pathway. Lithium, an inhibitor of GSK-3beta, mimics WNT-7a in granule cells. Here we examined further the effect of GSK-3beta inhibition on cytoskeletal re-organisation. Lithium induces axonal spreading and increases growth cone area and perimeter. This effect is associated with the absence or reduction of stable microtubules in spread areas. Lithium induces the loss of a phosphorylated form of MAP-1B, a microtubule associated protein involved in axonal outgrowth. Down-regulation of the phosphorylated MAP-1B, MAP-1B-P, from axonal processes occurs before axonal remodelling is evident. In vitro phosphorylation assays show that MAP-1B-P is generated by direct phosphorylation of MAP-1B by GSK-3beta. WNT-7a, like lithium, also leads to loss of MAP-1B-P from spread axons and growth cones. Our data suggest that WNT-7a and lithium induce changes in microtubule dynamics by inhibiting GSK-3beta which in turn lead to changes in the phosphorylation of MAP-1B. These findings suggest a novel role for GSK-3beta and WNTs in axonal remodelling and identify MAP-1B as a new target for GSK-3beta and WNT.
Lucas
F R
FR
Developmental Biology Research Centre, The Randall Institute, King's College London, 26-29 Drury Lane, London WC2B 5RL, UK.
Goold
R G
RG
Gordon-Weeks
P R
PR
Salinas
P C
PC
D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003599:Cytoskeleton / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3; D008094:Lithium / Q000494:pharmacology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051153:Wnt Proteins
D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; C490508:Wnt7a protein, mouse; D008094:Lithium; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3