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The Journal of Neuroscience, March 24, 2004, 24(12):3040-3050; doi:10.1523/JNEUROSCI.4934-03.2004

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Development/Plasticity/Repair
Protein Kinase A Activation Promotes Plasma Membrane Insertion of DCC from an Intracellular Pool: A Novel Mechanism Regulating Commissural Axon Extension

Jean-François Bouchard, Simon W. Moore, Nicolas X. Tritsch, Philippe P. Roux, Masoud Shekarabi, Philip A. Barker, and Timothy E. Kennedy

Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4 Canada

Protein kinase A (PKA) exerts a profound influence on axon extension during development and regeneration; however, the molecular mechanisms underlying these effects of PKA are not understood. Here, we show that DCC (deleted in colorectal cancer), a receptor for the axon guidance cue netrin-1, is distributed both at the plasma membrane and in a pre-existing intracellular vesicular pool in embryonic rat spinal commissural neurons. We hypothesized that the intracellular pool of DCC could be mobilized to the plasma membrane and enhance the response to netrin-1. Consistent with this, we show that application of netrin-1 causes a modest increase in cell surface DCC, without increasing the intracellular concentration of cAMP or activating PKA. Intriguingly, activation of PKA enhances the effect of netrin-1 on DCC mobilization and increases axon extension in response to netrin-1. PKA-dependent mobilization of DCC to the plasma membrane is selective, because the distributions of transient axonal glycoprotein-1, neural cell adhesion molecule, and trkB are not altered by PKA in these cells. Inhibiting adenylate cyclase, PKA, or exocytosis blocks DCC translocation on PKA activation. These findings indicate that netrin-1 increases the amount of cell surface DCC, that PKA potentiates the mobilization of DCC to the neuronal plasma membrane from an intracellular vesicular store, and that translocation of DCC to the cell surface increases axon outgrowth in response to netrin-1.

Key words: exocytosis; growth cone; regeneration; cAMP; endocytosis; outgrowth

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Received Nov 4, 2003; revised February 17, 2004; accepted February 18, 2004.

This article has been cited by other articles:

				S. W. Moore, J. P. Correia, K. Lai Wing Sun, M. Pool, A. E. Fournier, and T. E. Kennedy Rho inhibition recruits DCC to the neuronal plasma membrane and enhances axon chemoattraction to netrin 1 Development, September 1, 2008; 135(17): 2855 - 2864. [Abstract] [Full Text] [PDF]

				S. W. Moore, K. Lai Wing Sun, F. Xie, P. A. Barker, M. Conti, and T. E. Kennedy Soluble Adenylyl Cyclase Is Not Required for Axon Guidance to Netrin-1 J. Neurosci., April 9, 2008; 28(15): 3920 - 3924. [Abstract] [Full Text] [PDF]

				F. Moret, C. Renaudot, M. Bozon, and V. Castellani Semaphorin and neuropilin co-expression in motoneurons sets axon sensitivity to environmental semaphorin sources during motor axon pathfinding Development, December 15, 2007; 134(24): 4491 - 4501. [Abstract] [Full Text] [PDF]

				Y. Matsumoto, F. Irie, M. Inatani, M. Tessier-Lavigne, and Y. Yamaguchi Netrin-1/DCC Signaling in Commissural Axon Guidance Requires Cell-Autonomous Expression of Heparan Sulfate J. Neurosci., April 18, 2007; 27(16): 4342 - 4350. [Abstract] [Full Text] [PDF]

				K. Hayashida, D. R. Johnston, O. Goldberger, and P. W. Park Syndecan-1 Expression in Epithelial Cells Is Induced by Transforming Growth Factor beta through a PKA-dependent Pathway J. Biol. Chem., August 25, 2006; 281(34): 24365 - 24374. [Abstract] [Full Text] [PDF]

				J. L. Bartoe, W. L. McKenna, T. K. Quan, B. K. Stafford, J. A. Moore, J. Xia, K. Takamiya, R. L. Huganir, and L. Hinck Protein interacting with C-kinase 1/protein kinase Calpha-mediated endocytosis converts netrin-1-mediated repulsion to attraction. J. Neurosci., March 22, 2006; 26(12): 3192 - 3205. [Abstract] [Full Text] [PDF]

				S. W. Moore and T. E. Kennedy Protein Kinase A Regulates the Sensitivity of Spinal Commissural Axon Turning to Netrin-1 But Does Not Switch between Chemoattraction and Chemorepulsion J. Neurosci., March 1, 2006; 26(9): 2419 - 2423. [Abstract] [Full Text] [PDF]

				M. Shekarabi, S. W. Moore, N. X. Tritsch, S. J. Morris, J.-F. Bouchard, and T. E. Kennedy 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 J. Neurosci., March 23, 2005; 25(12): 3132 - 3141. [Abstract] [Full Text] [PDF]

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