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

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          Abstract

          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.

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          Most cited references39

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          The molecular biology of axon guidance.

          Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and molecules that direct this pathfinding are the topics of this review. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems.
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            Hybridization of bird species.

            Hybridization, the interbreeding of species, provides favorable conditions for major and rapid evolution to occur. In birds it is widespread. Approximately one in ten species is known to hybridize, and the true global incidence is likely to be much higher. A longitudinal study of Darwin's finch populations on a Galápagos island shows that hybrids exhibit higher fitness than the parental species over several years. Hybrids may be at an occasional disadvantage for ecological rather than genetic reasons in this climatically fluctuating environment. Hybridization presents challenges to the reconstruction of phylogenies, formulation of biological species concepts and definitions, and the practice of biological conservation.
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              Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates.

              In Drosophila, plexin A is a functional receptor for semaphorin-1a. Here we show that the human plexin gene family comprises at least nine members in four subfamilies. Plexin-B1 is a receptor for the transmembrane semaphorin Sema4D (CD100), and plexin-C1 is a receptor for the GPI-anchored semaphorin Sema7A (Sema-K1). Secreted (class 3) semaphorins do not bind directly to plexins, but rather plexins associate with neuropilins, coreceptors for these semaphorins. Plexins are widely expressed: in neurons, the expression of a truncated plexin-A1 protein blocks axon repulsion by Sema3A. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro. We conclude that plexins are receptors for multiple (and perhaps all) classes of semaphorins, either alone or in combination with neuropilins, and trigger a novel signal transduction pathway controlling cell repulsion.
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                Author and article information

                Journal
                J Cell Biol
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                22 November 2004
                : 167
                : 4
                : 687-698
                Affiliations
                [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
                Author notes

                Correspondence to Nathalie Lamarche-Vane: nathalie.lamarche@ 123456mcgill.ca

                Article
                200405053
                10.1083/jcb.200405053
                2172574
                15557120
                ae77b1fa-bbb5-4ec1-bfcc-bcaae7ec39ac
                Copyright © 2004, The Rockefeller University Press
                History
                : 10 May 2004
                : 17 September 2004
                Categories
                Research Articles
                Article

                Cell biology
                Cell biology

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