Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Originally published in Science Express on 8 February 2001
Science 9 March 2001:
Vol. 291. no. 5510, pp. 1928 - 1938
DOI: 10.1126/science.1058445
Prev | Table of Contents | Next

Research Articles

Hierarchical Organization of Guidance Receptors: Silencing of Netrin Attraction by Slit Through a Robo/DCC Receptor Complex

Elke Stein, Marc Tessier-Lavigne*

Axonal growth cones that cross the nervous system midline change their responsiveness to midline guidance cues: They become repelled by the repellent Slit and simultaneously lose responsiveness to the attractant netrin. These mutually reinforcing changes help to expel growth cones from the midline by making a once-attractive environment appear repulsive. Here, we provide evidence that these two changes are causally linked: In the growth cones of embryonic Xenopus spinal axons, activation of the Slit receptor Roundabout (Robo) silences the attractive effect of netrin-1, but not its growth-stimulatory effect, through direct binding of the cytoplasmic domain of Robo to that of the netrin receptor DCC. Biologically, this hierarchical silencing mechanism helps to prevent a tug-of-war between attractive and repulsive signals in the growth cone that might cause confusion. Molecularly, silencing is enabled by a modular and interlocking design of the cytoplasmic domains of these potentially antagonistic receptors that predetermines the outcome of their simultaneous activation.

Department of Anatomy and Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
*   To whom correspondence should be addressed. E-mail: marctl{at}itsa.ucsf.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
A midline switch of receptor processing regulates commissural axon guidance in vertebrates.
H. Nawabi, A. Briancon-Marjollet, C. Clark, I. Sanyas, H. Takamatsu, T. Okuno, A. Kumanogoh, M. Bozon, K. Takeshima, Y. Yoshida, et al. (2010)
Genes & Dev. 24, 396-410
   Abstract »    Full Text »    PDF »
The N-Glycanase png-1 Acts to Limit Axon Branching during Organ Formation in Caenorhabditis elegans.
N. Habibi-Babadi, A. Su, C. E. de Carvalho, and A. Colavita (2010)
J. Neurosci. 30, 1766-1776
   Abstract »    Full Text »    PDF »
From Guidance Signals to Movement: Signaling Molecules Governing Growth Cone Turning.
K. Hong and M. Nishiyama (2010)
Neuroscientist 16, 65-78
   Abstract »    PDF »
Role of deleted in colon carcinoma in osteoarthritis and in chondrocyte migration.
T. Schubert, S. Kaufmann, A.-K. Wenke, S. Grassel, and A.-K. Bosserhoff (2009)
Rheumatology 48, 1435-1441
   Abstract »    Full Text »    PDF »
The Development of Developmental Neuroscience.
C. Mason (2009)
J. Neurosci. 29, 12735-12747
   Full Text »    PDF »
Netrin-DCC, Robo-Slit, and Heparan Sulfate Proteoglycans Coordinate Lateral Positioning of Longitudinal Dopaminergic Diencephalospinal Axons.
E. Kastenhuber, U. Kern, J. L. Bonkowsky, C.-B. Chien, W. Driever, and J. Schweitzer (2009)
J. Neurosci. 29, 8914-8926
   Abstract »    Full Text »    PDF »
A Frazzled/DCC-Dependent Transcriptional Switch Regulates Midline Axon Guidance.
L. Yang, D. S. Garbe, and G. J. Bashaw (2009)
Science 324, 944-947
   Abstract »    Full Text »    PDF »
Guidance of Vascular Development: Lessons From the Nervous System.
B. Larrivee, C. Freitas, S. Suchting, I. Brunet, and A. Eichmann (2009)
Circ. Res. 104, 428-441
   Abstract »    Full Text »    PDF »
Active involvement of Robo1 and Robo4 in filopodia formation and endothelial cell motility mediated via WASP and other actin nucleation-promoting factors.
H. Sheldon, M. Andre, J. A. Legg, P. Heal, J. M. Herbert, R. Sainson, A. S. Sharma, J. K. Kitajewski, V. L. Heath, and R. Bicknell (2009)
FASEB J 23, 513-522
   Abstract »    Full Text »    PDF »
Pioneer longitudinal axons navigate using floor plate and Slit/Robo signals.
W. T. Farmer, A. L. Altick, H. F. Nural, J. P. Dugan, T. Kidd, F. Charron, and G. S. Mastick (2008)
Development 135, 3643-3653
   Abstract »    Full Text »    PDF »
Novel Regulated Expression of the SLIT/ROBO Pathway in the Ovary: Possible Role during Luteolysis in Women.
R. E. Dickinson, M. Myers, and W. C. Duncan (2008)
Endocrinology 149, 5024-5034
   Abstract »    Full Text »    PDF »
Manipulating Robo Expression In Vivo Perturbs Commissural Axon Pathfinding in the Chick Spinal Cord.
S. L. Reeber, N. Sakai, Y. Nakada, J. Dumas, K. Dobrenis, J. E. Johnson, and Z. Kaprielian (2008)
J. Neurosci. 28, 8698-8708
   Abstract »    Full Text »    PDF »
Genome-wide linkage scan for loci of musical aptitude in Finnish families: evidence for a major locus at 4q22.
K Pulli, K Karma, R Norio, P Sistonen, H H H Goring, and I Jarvela (2008)
J. Med. Genet. 45, 451-456
   Abstract »    Full Text »    PDF »
CLEC-38, A Transmembrane Protein with C-Type Lectin-Like Domains, Negatively Regulates UNC-40-Mediated Axon Outgrowth and Promotes Presynaptic Development in Caenorhabditis elegans.
G. Kulkarni, H. Li, and W. G. Wadsworth (2008)
J. Neurosci. 28, 4541-4550
   Abstract »    Full Text »    PDF »
RPM-1, a Caenorhabditis elegans Protein That Functions in Presynaptic Differentiation, Negatively Regulates Axon Outgrowth by Controlling SAX-3/robo and UNC-5/UNC5 Activity.
H. Li, G. Kulkarni, and W. G. Wadsworth (2008)
J. Neurosci. 28, 3595-3603
   Abstract »    Full Text »    PDF »
Phosphatidylinositol-3-Kinase-Atypical Protein Kinase C Signaling Is Required for Wnt Attraction and Anterior-Posterior Axon Guidance.
A. M. Wolf, A. I. Lyuksyutova, A. G. Fenstermaker, B. Shafer, C. G. Lo, and Y. Zou (2008)
J. Neurosci. 28, 3456-3467
   Abstract »    Full Text »    PDF »
The Slit Receptor EVA-1 Coactivates a SAX-3/Robo Mediated Guidance Signal in C. elegans.
K. Fujisawa, J. L. Wrana, and J. G. Culotti (2007)
Science 317, 1934-1938
   Abstract »    Full Text »    PDF »
Structural insights into the Slit-Robo complex.
C. Morlot, N. M. Thielens, R. B. G. Ravelli, W. Hemrika, R. A. Romijn, P. Gros, S. Cusack, and A. A. McCarthy (2007)
PNAS 104, 14923-14928
   Abstract »    Full Text »    PDF »
Slit-2/Robo-1 modulates the CXCL12/CXCR4-induced chemotaxis of T cells.
A. Prasad, Z. Qamri, J. Wu, and R. K. Ganju (2007)
J. Leukoc. Biol. 82, 465-476
   Abstract »    Full Text »    PDF »
Independent Functions of Slit-Robo Repulsion and Netrin-Frazzled Attraction Regulate Axon Crossing at the Midline in Drosophila.
D. S. Garbe and G. J. Bashaw (2007)
J. Neurosci. 27, 3584-3592
   Abstract »    Full Text »    PDF »
The Wnt Receptor Ryk Is Required for Wnt5a-Mediated Axon Guidance on the Contralateral Side of the Corpus Callosum.
T. R. Keeble, M. M. Halford, C. Seaman, N. Kee, M. Macheda, R. B. Anderson, S. A. Stacker, and H. M. Cooper (2006)
J. Neurosci. 26, 5840-5848
   Abstract »    Full Text »    PDF »
Semaphorin 3d guides laterality of retinal ganglion cell projections in zebrafish.
J. A. Sakai and M. C. Halloran (2006)
Development 133, 1035-1044
   Abstract »    Full Text »    PDF »
Slit2 and netrin 1 act synergistically as adhesive cues to generate tubular bi-layers during ductal morphogenesis.
P. Strickland, G. C. Shin, A. Plump, M. Tessier-Lavigne, and L. Hinck (2006)
Development 133, 823-832
   Abstract »    Full Text »    PDF »
Sema3a1 guides spinal motor axons in a cell- and stage-specific manner in zebrafish.
M. Sato-Maeda, H. Tawarayama, M. Obinata, J. Y. Kuwada, and W. Shoji (2006)
Development 133, 937-947
   Abstract »    Full Text »    PDF »
DCC-dependent Phospholipase C Signaling in Netrin-1-induced Neurite Elongation.
Y. Xie, Y. Hong, X.-Y. Ma, X.-R. Ren, S. Ackerman, L. Mei, and W.-C. Xiong (2006)
J. Biol. Chem. 281, 2605-2611
   Abstract »    Full Text »    PDF »
Multiple Eph Receptors and B-Class Ephrins Regulate Midline Crossing of Corpus Callosum Fibers in the Developing Mouse Forebrain.
S. W. Mendes, M. Henkemeyer, and D. J. Liebl (2006)
J. Neurosci. 26, 882-892
   Abstract »    Full Text »    PDF »
FAK and Src kinases are required for netrin-induced tyrosine phosphorylation of UNC5.
W. Li, J. Aurandt, C. Jurgensen, Y. Rao, and K.-L. Guan (2006)
J. Cell Sci. 119, 47-55
   Abstract »    Full Text »    PDF »
Sensitized genetic backgrounds reveal a role for C. elegans FGF EGL-17 as a repellent for migrating CAN neurons.
T. C. Fleming, F. W. Wolf, and G. Garriga (2005)
Development 132, 4857-4867
   Abstract »    Full Text »    PDF »
Slit-mediated repulsion is a key regulator of motor axon pathfinding in the hindbrain.
R. Hammond, V. Vivancos, A. Naeem, J. Chilton, E. Mambitisaeva, W. Andrews, V. Sundaresan, and S. Guthrie (2005)
Development 132, 4483-4495
   Abstract »    Full Text »    PDF »
The VAB-1 Eph receptor tyrosine kinase and SAX-3/Robo neuronal receptors function together during C. elegans embryonic morphogenesis.
S. Ghenea, J. R. Boudreau, N. P. Lague, and I. D. Chin-Sang (2005)
Development 132, 3679-3690
   Abstract »    Full Text »    PDF »
Novel brain wiring functions for classical morphogens: a role as graded positional cues in axon guidance.
F. Charron and M. Tessier-Lavigne (2005)
Development 132, 2251-2262
   Abstract »    Full Text »    PDF »
Slit-Roundabout Signaling Neutralizes Netrin-Frazzled-Mediated Attractant Cue to Specify the Lateral Positioning of Longitudinal Axon Pathways.
K. M. Bhat (2005)
Genetics 170, 149-159
   Abstract »    Full Text »    PDF »
DCC association with lipid rafts is required for netrin-1-mediated axon guidance.
Z. Herincs, V. Corset, N. Cahuzac, C. Furne, V. Castellani, A.-O. Hueber, and P. Mehlen (2005)
J. Cell Sci. 118, 1687-1692
   Abstract »    Full Text »    PDF »
Role of neural guidance signals in blood vessel navigation.
M. Autiero, F. De Smet, F. Claes, and P. Carmeliet (2005)
Cardiovasc Res 65, 629-638
   Abstract »    Full Text »    PDF »
Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance.
M. Meriane, J. Tcherkezian, C. A. Webber, E. I. Danek, I. Triki, S. McFarlane, E. Bloch-Gallego, and N. Lamarche-Vane (2004)
J. Cell Biol. 167, 687-698
   Abstract »    Full Text »    PDF »
The axonal attractant Netrin-1 is an angiogenic factor.
K. W. Park, D. Crouse, M. Lee, S. K. Karnik, L. K. Sorensen, K. J. Murphy, C. J. Kuo, and D. Y. Li (2004)
PNAS 101, 16210-16215
   Abstract »    Full Text »    PDF »
Caenorhabditis elegans VEM-1, a Novel Membrane Protein, Regulates the Guidance of Ventral Nerve Cord-Associated Axons.
E. Runko and Z. Kaprielian (2004)
J. Neurosci. 24, 9015-9026
   Abstract »    Full Text »    PDF »
Vilse, a conserved Rac/Cdc42 GAP mediating Robo repulsion in tracheal cells and axons.
A. Lundstrom, M. Gallio, C. Englund, P. Steneberg, J. Hemphala, P. Aspenstrom, K. Keleman, L. Falileeva, B. J. Dickson, and C. Samakovlis (2004)
Genes & Dev. 18, 2161-2171
   Abstract »    Full Text »    PDF »
Spatial patterns of gene expression in the olfactory bulb.
D. M. Lin, Y. H. Yang, J. A. Scolnick, L. J. Brunet, H. Marsh, V. Peng, Y. Okazaki, Y. Hayashizaki, T. P. Speed, and J. Ngai (2004)
PNAS 101, 12718-12723
   Abstract »    Full Text »    PDF »
Role of the Dependence Receptor DCC in Colorectal Cancer Pathogenesis.
P. Mehlen and E. R. Fearon (2004)
J. Clin. Oncol. 22, 3420-3428
   Abstract »    Full Text »    PDF »
Inhibition of Netrin-Mediated Axon Attraction by a Receptor Protein Tyrosine Phosphatase.
C. Chang, T. W. Yu, C. I. Bargmann, and M. Tessier-Lavigne (2004)
Science 305, 103-106
   Abstract »    Full Text »    PDF »
Mutations in a Human ROBO Gene Disrupt Hindbrain Axon Pathway Crossing and Morphogenesis.
J. C. Jen, W.-M. Chan, T. M. Bosley, J. Wan, J. R. Carr, U. Rub, D. Shattuck, G. Salamon, L. C. Kudo, J. Ou, et al. (2004)
Science 304, 1509-1513
   Abstract »    Full Text »    PDF »
The Drosophila ARF6-GEF Schizo controls commissure formation by regulating Slit.
S. Onel, L. Bolke, and C. Klambt (2004)
Development 131, 2587-2594
   Abstract »    Full Text »    PDF »
Positioning sensory terminals in the olfactory lobe of Drosophila by Robo signaling.
D. Jhaveri, S. Saharan, A. Sen, and V. Rodrigues (2004)
Development 131, 1903-1912
   Abstract »    Full Text »    PDF »
Slit Protein-mediated Inhibition of CXCR4-induced Chemotactic and Chemoinvasive Signaling Pathways in Breast Cancer Cells.
A. Prasad, A. Z. Fernandis, Y. Rao, and R. K. Ganju (2004)
J. Biol. Chem. 279, 9115-9124
   Abstract »    Full Text »    PDF »
L1/Laminin Modulation of Growth Cone Response to EphB Triggers Growth Pauses and Regulates the Microtubule Destabilizing Protein SCG10.
L. H. Suh, S. F. Oster, S. S. Soehrman, G. Grenningloh, and D. W. Sretavan (2004)
J. Neurosci. 24, 1976-1986
   Abstract »    Full Text »    PDF »
Multiple Roles for Slits in the Control of Cell Migration in the Rostral Migratory Stream.
K. T. Nguyen-Ba-Charvet, N. Picard-Riera, M. Tessier-Lavigne, A. Baron-Van Evercooren, C. Sotelo, and A. Chedotal (2004)
J. Neurosci. 24, 1497-1506
   Abstract »    Full Text »    PDF »
Semaphorin 3F Antagonizes Neurotrophin-Induced Phosphatidylinositol 3-Kinase and Mitogen-Activated Protein Kinase Kinase Signaling: A Mechanism for Growth Cone Collapse.
J. K. Atwal, K. K. Singh, M. Tessier-Lavigne, F. D. Miller, and D. R. Kaplan (2003)
J. Neurosci. 23, 7602-7609
   Abstract »    Full Text »    PDF »
Signaling Receptome: A Genomic and Evolutionary Perspective of Plasma Membrane Receptors Involved in Signal Transduction.
I. Ben-Shlomo, S. Yu Hsu, R. Rauch, H. W. Kowalski, and A. J. W. Hsueh (2003)
Sci. STKE 2003, re9
   Abstract »    Full Text »    PDF »
Distinguishing between Directional Guidance and Motility Regulation in Neuronal Migration.
M. Ward, C. McCann, M. DeWulf, J. Y. Wu, and Y. Rao (2003)
J. Neurosci. 23, 5170-5177
   Abstract »    Full Text »    PDF »
Chemotropic Molecules: Guides for Axonal Pathfinding and Cell Migration During CNS Development.
F. de Castro (2003)
Physiology 18, 130-136
   Abstract »    Full Text »    PDF »
Connecting the eye to the brain: the molecular basis of ganglion cell axon guidance.
S F Oster and D W Sretavan (2003)
Br J Ophthalmol 87, 639-645
   Abstract »    Full Text »    PDF »
Growth Cones Integrate Signaling from Multiple Guidance Cues.
V. D. Dontchev and P. C. Letourneau (2003)
J. Histochem. Cytochem. 51, 435-444
   Abstract »    Full Text »    PDF »
The migration of cerebellar rhombic lip derivatives.
J. D. Gilthorpe, E.-K. Papantoniou, A. Chedotal, A. Lumsden, and R. J. T. Wingate (2003)
Development 129, 4719-4728
   Abstract »    Full Text »    PDF »
Dephrin, a transmembrane ephrin with a unique structure, prevents interneuronal axons from exiting the Drosophila embryonic CNS.
T. Bossing and A. H. Brand (2003)
Development 129, 4205-4218
   Abstract »    Full Text »    PDF »
Commissureless is required both in commissural neurones and midline cells for axon guidance across the midline.
M. Georgiou and G. Tear (2003)
Development 129, 2947-2956
   Abstract »    Full Text »    PDF »
A combination of chain and neurophilic migration involving the adhesion molecule TAG-1 in the caudal medulla.
K. Kyriakopoulou, I. de Diego, M. Wassef, and D. Karagogeos (2003)
Development 129, 287-296
   Abstract »    Full Text »    PDF »
Multiple influences on the migration of precerebellar neurons in the caudal medulla.
I. de Diego, K. Kyriakopoulou, D. Karagogeos, and M. Wassef (2003)
Development 129, 297-306
   Abstract »    Full Text »    PDF »
SLIT2 Axon Guidance Molecule Is Frequently Inactivated in Colorectal Cancer and Suppresses Growth of Colorectal Carcinoma Cells.
A. Dallol, D. Morton, E. R. Maher, and F. Latif (2003)
Cancer Res. 63, 1054-1058
   Abstract »    Full Text »    PDF »
Invariant Sema5A inhibition serves an ensheathing function during optic nerve development.
S. F. Oster, M. O. Bodeker, F. He, and D. W. Sretavan (2003)
Development 130, 775-784
   Abstract »    Full Text »    PDF »
Molecular Mechanisms of Axon Guidance.
B. J. Dickson (2002)
Science 298, 1959-1964
   Abstract »    Full Text »    PDF »
The Netrin 1 Receptors Unc5h3 and Dcc Are Necessary at Multiple Choice Points for the Guidance of Corticospinal Tract Axons.
J. H. Finger, R. T. Bronson, B. Harris, K. Johnson, S. A. Przyborski, and S. L. Ackerman (2002)
J. Neurosci. 22, 10346-10356
   Abstract »    Full Text »    PDF »
SLIT2, a Human Homologue of the Drosophila Slit2 Gene, Has Tumor Suppressor Activity and Is Frequently Inactivated in Lung and Breast Cancers.
A. Dallol, N. F. Da Silva, P. Viacava, J. D. Minna, I. Bieche, E. R. Maher, and F. Latif (2002)
Cancer Res. 62, 5874-5880
   Abstract »    Full Text »    PDF »
Targeting Axons to Specific Fiber Tracts In Vivo by Altering Cadherin Expression.
U. Treubert-Zimmermann, D. Heyers, and C. Redies (2002)
J. Neurosci. 22, 7617-7626
   Abstract »    Full Text »    PDF »
Nerve Growth Factor and Semaphorin 3A Signaling Pathways Interact in Regulating Sensory Neuronal Growth Cone Motility.
V. D. Dontchev and P. C. Letourneau (2002)
J. Neurosci. 22, 6659-6669
   Abstract »    Full Text »    PDF »
Regulation by Protein Kinase A Switching of Axonal Pathfinding of Zebrafish Olfactory Sensory Neurons through the Olfactory Placode-Olfactory Bulb Boundary.
T. Yoshida, A. Ito, N. Matsuda, and M. Mishina (2002)
J. Neurosci. 22, 4964-4972
   Abstract »    Full Text »    PDF »
Integrins Regulate Responsiveness to Slit Repellent Signals.
A. Stevens and J. R. Jacobs (2002)
J. Neurosci. 22, 4448-4455
   Abstract »    Full Text »    PDF »
Altered Levels of Gq Activity Modulate Axonal Pathfinding in Drosophila.
A. Ratnaparkhi, S. Banerjee, and G. Hasan (2002)
J. Neurosci. 22, 4499-4508
   Abstract »    Full Text »    PDF »
The C Domain of Netrin UNC-6 Silences Calcium/Calmodulin-Dependent Protein Kinase- and Diacylglycerol-Dependent Axon Branching in Caenorhabditis elegans.
Q. Wang and W. G. Wadsworth (2002)
J. Neurosci. 22, 2274-2282
   Abstract »    Full Text »    PDF »
Genetic effects on human cognition: lessons from the study of mental retardation syndromes.
P Nokelainen and J Flint (2002)
J. Neurol. Neurosurg. Psychiatry 72, 287-296
   Abstract »    Full Text »    PDF »
Axon Navigation in the Mammalian Primary Olfactory Pathway: Where to Next?.
B. Key and J. St John (2002)
Chem Senses 27, 245-260
   Abstract »    Full Text »    PDF »
Attractive and repulsive functions of Slit are mediated by different receptors in the Drosophila trachea.
C. Englund, P. Steneberg, L. Falileeva, N. Xylourgidis, and C. Samakovlis (2002)
Development 129, 4941-4951
   Abstract »    Full Text »    PDF »
Gliolectin-mediated carbohydrate binding at the Drosophila midline ensures the fidelity of axon pathfinding.
M. Sharrow and M. Tiemeyer (2001)
Development 128, 4585-4595
   Abstract »    Full Text »    PDF »
Extracellular Signals That Regulate the Tangential Migration of Olfactory Bulb Neuronal Precursors: Inducers, Inhibitors, and Repellents.
H. A. Mason, S. Ito, and G. Corfas (2001)
J. Neurosci. 21, 7654-7663
   Abstract »    Full Text »    PDF »
Astrocytes from Cerebral Cortex or Striatum Attract Adult Host Serotoninergic Axons into Intrastriatal Ventral Mesencephalic Co-Grafts.
A. Petit, P. Pierret, A. Vallee, and G. Doucet (2001)
J. Neurosci. 21, 7182-7193
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)