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The Journal of Neuroscience, March 23, 2005, 25(12):3132-3141; doi:10.1523/JNEUROSCI.1920-04.2005

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Cellular/Molecular
Deleted in Colorectal Cancer Binding Netrin-1 Mediates Cell Substrate Adhesion and Recruits Cdc42, Rac1, Pak1, and N-WASP into an Intracellular Signaling Complex That Promotes Growth Cone Expansion

Masoud Shekarabi, Simon W. Moore, Nicolas X. Tritsch, Stephen J. Morris, Jean-Francois Bouchard, and Timothy E. Kennedy

Center for Neuronal Survival, Montréal Neurological Institute, McGill University, Montréal, Québec, Canada H3A 2B4

Extracellular cues direct axon extension by regulating growth cone morphology. The netrin-1 receptor deleted in colorectal cancer (DCC) is required for commissural axon extension to the floor plate in the embryonic spinal cord. Here we demonstrate that challenging embryonic rat spinal commissural neurons with netrin-1, either in solution or as a substrate, causes DCC-dependent increases in growth cone surface area and filopodia number, which we term growth cone expansion. We provide evidence that DCC influences growth cone morphology by at least two mechanisms. First, DCC mediates an adhesive interaction with substrate-bound netrin-1. Second, netrin-1 binding to DCC recruits an intracellular signaling complex that directs the organization of actin. We show that netrin-1-induced growth cone expansion requires Cdc42 (cell division cycle 42), Rac1 (Ras-related C3 botulinum toxin substrate 1), Pak1 (p21-activated kinase), and N-WASP (neuronal Wiskott-Aldrich syndrome protein) and that the application of netrin-1 rapidly activates Cdc42, Rac1, and Pak1. Furthermore, netrin-1 recruits Cdc42, Rac1, Pak1, and N-WASP into a complex with the intracellular domain of DCC and Nck1. These findings suggest that DCC influences growth cone morphology by acting both as a transmembrane bridge that links extracellular netrin-1 to the actin cytoskeleton and as the core of a protein complex that directs the organization of actin.

Key words: embryonic spinal commissural neuron; chemotropism; chemotropic; axon guidance; motility; DCC; netrin

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Received May 17, 2004; revised February 2, 2005; accepted February 9, 2005.

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