Wnt regulates axon behavior through changes in microtubule growth directionality: a new role for adenomatous polyposis coli.
Axon guidance and target-derived signals control axonal behavior by regulating the cytoskeleton through poorly defined mechanisms. In particular, how these signaling molecules regulate the growth and directionality of microtubules is not well understood. Here we examine the effect of Wnts on growth cone remodeling, a process that precedes synapse formation. Time-lapse recordings reveal that Wnt3a rapidly inhibits growth cone translocation while inducing growth cone enlargement. These changes in axonal behavior are associated with changes in the organization of microtubules. Time-lapse imaging of EB3-GFP (green fluorescent protein)-labeled microtubule plus-ends demonstrates that Wnt3a regulates microtubule directionality, resulting in microtubule looping, growth cone pausing, and remodeling. Analyses of Dishevelled-1 (Dvl1) mutant neurons demonstrate that Dvl1 is required for Wnt-mediated microtubule reorganization and axon remodeling. Wnt signaling directly affects the microtubule cytoskeleton by unexpectedly inducing adenomatous polyposis coli (APC) loss from microtubule plus-ends. Consistently, short hairpin RNA knockdown of APC mimics Wnt3a function. Together, our findings define APC as a key Wnt signaling target in the regulation of microtubule growth direction.
Purro
Silvia A
SA
Research Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom.
Ciani
Lorenza
L
Hoyos-Flight
Monica
M
Stamatakou
Eleanna
E
Siomou
Eliza
E
Salinas
Patricia C
PC
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000502:physiology*; D002478:Cells, Cultured; D000072261:Dishevelled Proteins; D015536:Down-Regulation / Q000502:physiology; D004622:Embryo, Mammalian; D005727:Ganglia, Spinal / Q000166:cytology; D020439:Growth Cones / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D009475:Neurons, Afferent / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology; D020033:Protein Isoforms / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D014162:Transfection; D051153:Wnt Proteins / Q000502:physiology*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; D010750:Phosphoproteins; D020033:Protein Isoforms; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin