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The Journal of Neuroscience, August 20, 2008, 28(34):8644-8654; doi:10.1523/JNEUROSCI.2320-08.2008

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Cellular/Molecular
Wnt Regulates Axon Behavior through Changes in Microtubule Growth Directionality: A New Role for Adenomatous Polyposis Coli

Silvia A. Purro, ^* Lorenza Ciani, ^* Monica Hoyos-Flight, ^* Eleanna Stamatakou, Eliza Siomou, and Patricia C. Salinas

Research Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom

Correspondence should be addressed to Patricia C. Salinas, Research Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK. Email: p.salinas{at}ucl.ac.uk

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.

Key words: neurons; Wnt; Dishevelled; Gsk3; microtubules; APC

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Received July 18, 2008; revised June 26, 2008; accepted July 11, 2008.

Correspondence should be addressed to Patricia C. Salinas, Research Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK. Email: p.salinas{at}ucl.ac.uk

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