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Published 22 November 2004. doi:10.1083/jcb.200405053
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 4, 687-698
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Article

Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance



Mayya Meriane1, Joseph Tcherkezian1, Christine A. Webber2, Eric I. Danek1, Ibtissem Triki1, Sarah McFarlane2, Evelyne Bloch-Gallego3, and Nathalie Lamarche-Vane1

1 Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada H3A 2B2
2 Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta, Canada T2N 4N1
3 Génétique, Développement et Pathologie Moléculaire, Institut Cochin, INSERM U 567, CNRS UMR 8104, 75014 Paris Cedex 05, France

Correspondence to Nathalie Lamarche-Vane: nathalie.lamarche{at}mcgill.ca

Netrin-1 acts as a chemoattractant molecule to guide commissural neurons (CN) toward the floor plate by interacting with the receptor deleted in colorectal cancer (DCC). The molecular mechanisms underlying Netrin-1–DCC signaling are still poorly characterized. Here, we show that DCC is phosphorylated in vivo on tyrosine residues in response to Netrin-1 stimulation of CN and that the Src family kinase inhibitors PP2 and SU6656 block both Netrin-1–dependent phosphorylation of DCC and axon outgrowth. PP2 also blocks the reorientation of Xenopus laevis retinal ganglion cells that occurs in response to Netrin-1, which suggests an essential role of the Src kinases in Netrin-1–dependent orientation. Fyn, but not Src, is able to phosphorylate the intracellular domain of DCC in vitro, and we demonstrate that Y1418 is crucial for DCC axon outgrowth function. Both DCC phosphorylation and Netrin-1–induced axon outgrowth are impaired in Fyn–/– CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1.

M. Meriane and J. Tcherkezian contributed equally to this paper.

Abbreviations used in this paper: CA, constitutively active; CN, commissural neurons; CNS, central nervous system; DCC, deleted in colorectal cancer; DCC-C, cytoplasmic domain of DCC; DN, dominant negative; E, embryonic day; GST-PAK, p65PAK fused to GST; pY, phosphotyrosine; RGC, retinal ganglion cells; UNC, uncoordinated.


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