Modulation of Semaphorin Signaling by Ig Superfamily Cell Adhesion Molecules

  • Ahmad Bechara
  • Julien Falk
  • Frédéric Moret
  • Valérie Castellani
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 600)


During axon navigation, growth cones continuously interact with molecular cues in their environment, some of which control adherence and bundle assembly, others axon elongation and direction. Growth cone responses to these different environmental cues are tightly coordinated during the development of neuronal projections. Several recent studies show that axon sensitivity to guidance cues is modulated by extracellular and intracellular signals. This regulation may enable different classes of cues to combine their effects and may also represent important means for diversifying pathway choices and for compensating for the limited number of guidance cues. This chapter focuses on the modulation exerted by Ig Superfamily cell adhesion molecules (IgSFCAMs) on guidance cues of the class III secreted semaphorins


Growth Cone Transfected COS7 Cell Commissural Axon Growth Cone Collapse Dorsal Root Entry Zone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Song HJ, Poo MM. signal transduction underlying growth cone guidance by diffusible factors. Curr Opin Neurobiol 1999; (3):355–63.Google Scholar
  2. 2.
    Luo Y, Raible D, Raper JA. Collapsin: A protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 1993; 75(2):217–27.PubMedCrossRefGoogle Scholar
  3. 3.
    Kolodkin AL, Matthes DJ, Goodman CS. The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 1993; 75(7):1389–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Raper JA. semaphorins and their receptors in vertebrates and invertebrates. Curr Opin Neurobiol 2000; 10(1):88–94.PubMedCrossRefGoogle Scholar
  5. 5.
    Stevens CB, Halloran MC. Developmental expression of sema3G, a novel zebrafish semaphorin. Gene Expr Patterns 2005; 5(5):647–53.PubMedCrossRefGoogle Scholar
  6. 6.
    Taniguchi M, Masuda T, Fukaya M et al. Identification and characterization of a novel member of murine semaphorin family. Genes Cells 2005; 10(8):785–92.PubMedCrossRefGoogle Scholar
  7. 7.
    Bagnard D, Lohrum M, Uziel D et al. semaphorins act as attractive and repulsive guidance signals during the development of cortical projections. Development 1998; 125:5043–5053.PubMedGoogle Scholar
  8. 8.
    de Castro F, Hu L, Drabkin H et al. Chemoattraction and chemorepulsion of olfactory bulb axons by different secreted semaphorins. J Neurosci 1999; 19:4428–36.PubMedGoogle Scholar
  9. 9.
    Wolman MA, Liu Y, Tawarayama H et al. Repulsion and attraction of axons by semaphorin 3D are mediated by different neuropilins in vivo. J Neurosci 2004; 24:8428–8435.PubMedCrossRefGoogle Scholar
  10. 10.
    Falk J, Bechara A, Fiore R et al. Dual functional activity of semaphorin 3B is required for positioning the anterior commissure. Neuron 2005; 48(1):63–75.PubMedCrossRefGoogle Scholar
  11. 11.
    Castellani V, Chedotal A, Schachner M et al. Analysis of the L1-deficient mouse phenotype reveals cross-talk between Sema3A and L1 signaling pathways in axonal guidance. Neuron 2000; 27:237–249.PubMedCrossRefGoogle Scholar
  12. 12.
    Brummendorf T, Rathjen FG. Structure function relationships of axon-associated adhesion receptors of the immunoglobulin superfamily. Curr Opin Neurobiol 1996; 6(5):584–93.PubMedCrossRefGoogle Scholar
  13. 13.
    Kamiguchi H, Lemmon V. IgCAMs: Bidirectional signals underlying neurite growth. Curr Opin Cell Biol 2000; 12(5):598–60.PubMedCrossRefGoogle Scholar
  14. 14.
    Brummendorf T, Lemmon V. Immunoglobulin superfamily receptors: Cis-interactions, intracellular adapters and alternative splicing regulate adhesion. Curr Opin Cell Biol 2001; 13:611.PubMedCrossRefGoogle Scholar
  15. 15.
    Rougon G, Hobert O. New insights into the diversity and function of neuronal immunoglobulin superfamily molecules. Annu Rev Neurosci 2003; 26:207–38.PubMedCrossRefGoogle Scholar
  16. 16.
    Brummendorf T, Kenwrick S, Rathjen FG. Neural cell recognition molecule L1: From cell biology to human hereditary brain malformations. Curr Opin Neurobiol 1998; 8(1):87–97.PubMedCrossRefGoogle Scholar
  17. 17.
    Dickson TC, Mintz CD, Benson DL et al. Functional binding interaction identified between the axonal CAM L1 and members of the ERM family. J Cell Biol 2002; 24:1105–12.CrossRefGoogle Scholar
  18. 18.
    Volkmer H, Hassel B, Wolff JM et al. Structure of the axonal surface recognition molecule neurofascin and its relationship to a neural subgroup of the immunoglobulin superfamily. J Cell Biol 1992; 118(1):149–61.PubMedCrossRefGoogle Scholar
  19. 19.
    Gutwein P, Oleszewski M, Mechtersheimer S et al. Role of Src kinases in the ADAM-mediated release of L1 adhesion molecule from human tumor cells. J Biol Chem 2000; 275(20):15490–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Silletti S, Mei F, Sheppard D et al. Plasmin-sensitive dibasic sequences in the third fibronectin-like domain of L1-cell adhesion molecule (CAM) facilitate homomultimerization and concomitant integrin recruitment. J Cell Biol 2000; 149(7):1485–50.PubMedCrossRefGoogle Scholar
  21. 21.
    Mechtersheimer S, Gutwein P, Agmon-Levin N et al. Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins. J Cell Biol 2001; 155(4):661–73.PubMedCrossRefGoogle Scholar
  22. 22.
    Gutwein P, Mechtersheimer S, Riedle S et al. ADAM10-mediated clevage of L1 adhesion molecule at the cell surface and in released membrane vesicles. FASEB J 2003; 17(2):292–4.PubMedGoogle Scholar
  23. 23.
    Xu YZ, Ji Y, Zipser B et al. Proteolytic cleavage of the ectodomain of the L1 CAM family member Tractin. J Biol Chem 2003; 278(6):4322–30.PubMedCrossRefGoogle Scholar
  24. 24.
    Naus S, Richter M, Wildeboer D et al. Ectodomain shedding of the neural recognition molecule CHL1 by the metalloprotease-disintegrin ADAM8 promotes neurite outgrowth and suppresses neuronal cell death. J Biol Chem 2004; 279(16):16083–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Conacci-Sorrell M, Kaplan A, Raveh S et al. The Shed Ectodomain of Nr-CAM stimulates cell proliferation and motility, and confers cell transformation. Cancer Res 2005; 65(24):11605–12.PubMedCrossRefGoogle Scholar
  26. 26.
    Maretzky T, Schulte M, Ludwig A et al. L1 is sequentially processed by two differently activated metalloproteases and Presenilin/gamma-secretase and regulates neural cell adhesion, cell migration, and neurite outgrowth. Mol Cell Biol 2005; 25(20):9040–53.PubMedCrossRefGoogle Scholar
  27. 27.
    McFarlane S. Metalloproteases: Carving out a role in axon guidance. Neuron 2003; 37(4):559–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Hattori M, Osterfield M, Flanagan JG. Regulated cleavage of a contact-mediated axon repellent. Science 2000; 289(5483):1360–5.PubMedCrossRefGoogle Scholar
  29. 29.
    Galko MJ, Tessier-Lavigne M. Function of an axonal chemoattractant modulated by metalloprotease activity. Science 2000; 289(5483):1365–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Fambrough D, Pan D, Rubin GM et al. The cell surface metalloprotease/disintegrin Kuzbanian is required for axonal extension in Drosophila. Proc Natl Acad Sci USA 1996; 93(23):13233–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Schimmelpfeng K, Gogel S, Klambt C. The function of leak and kuzbanian during growth cone and cell migration. Mech Dev 2001; 106(1–2):25–36.PubMedCrossRefGoogle Scholar
  32. 32.
    Hehr CL, Hocking JC, McFarlane S. Matrix metalloproteinases are required for retinal ganglion cell axon guidance at select decision points. Development 2005; 132(15):3371–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Kayyem JF, Roman JM, de la Rosa EJ et al. Bravo/Nr-CAM is closely related to the cell adhesion molecules L1 and Ng-CAM and has a similar heterodimer structure. J Cell Biol 1992; 118(5):1259–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Volkmer H, Hassel B, Wolff JM et al. Structure of the axonal surface recognition molecule neurofascin and its relationship to a neural subgroup of the immunoglobulin superfamily. J Cell Biol 1992; 118(1):149–61.PubMedCrossRefGoogle Scholar
  35. 35.
    Tamagnone L, Comoglio PM. Signaling by semaphorin receptors: Cell guidance and beyond. Trends Cell Biol 2000; 10:377–383.PubMedCrossRefGoogle Scholar
  36. 36.
    Castellani V, De Angelis E, Kenwrick S et al. Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A. EMBO J 2002; 21:6348–6357.PubMedCrossRefGoogle Scholar
  37. 37.
    Itoh K, Cheng L, Kamei Y et al. Brain development in mice lacking L1-L1 homophilic adhesion. J Cell Biol 2004; 165(1):145–54.PubMedCrossRefGoogle Scholar
  38. 38.
    Fouriner AE, Nakamura F, Kawamoto S et al. semaphorin3A enhances endocytosis at sites of receptor-F-actin colocalization during growth cone collapse. J Cell Biol 2000; 149(2):411–22.CrossRefGoogle Scholar
  39. 39.
    Jurney WM, Gallo G, Letourneau PC et al. Racl-mediated endocytosis during ephrin-A2-and semaphorin 3A-induced growth cone collapse. J Neurosci 2002; 22(14):6019–28.PubMedGoogle Scholar
  40. 40.
    Piper M, Salih S, Weinl C et al. Endocytosis-dependent desensitization and protein synthesis-dependent resensitization in retinal growth cone adaptation. Nat Neurosci 2005; 8(2):179–86.PubMedCrossRefGoogle Scholar
  41. 41.
    Kamiguchi H, Long KE, Pendergast M et al. The neural cell adhesion molecule L1 interacts with the AP-2 adaptor and is endocytosed via the clathrin-mediated pathway. J Neurosci 1998; 18(14):5311–21.PubMedGoogle Scholar
  42. 42.
    Kamiguchi H, Lemmon V. Recycling of the cell adhesion molecule L1 in axonal growth cones. J Neurosci 2000; 20(10):3676–86.PubMedGoogle Scholar
  43. 43.
    Reid RA, Hemperly JJ. Variants of human L1 cell adhesion molecule arise through alternate splicing of RNA. J Mol Neurosci 1992; 3(3):127–35.PubMedCrossRefGoogle Scholar
  44. 44.
    Schaefer AW, Kamei Y, Kamiguchi H et al. L1 endocytosis is controlled by a phosphorylation-dephosphorylation cycle stimulated by outside-in signaling by L1. J Cell Biol 2002; 157(7):1223–32.PubMedCrossRefGoogle Scholar
  45. 45.
    Castellani V, Falk J, Rougon G. semaphorin3A-induced receptor endocytosis during axon guidance responses is mediated by L1 CAM. Mol Cell Neurosci 2004; 26(1):89–10.PubMedCrossRefGoogle Scholar
  46. 46.
    Nishimura T, Fukata Y, Kato K et al. CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth. Nat Cell Biol 2003; 5: 819–26.PubMedCrossRefGoogle Scholar
  47. 47.
    McPherson PS, Kay BK, Hussain NK. Signaling on the endocytic pathway. Traffic 2001; 2(6):375–84.PubMedCrossRefGoogle Scholar
  48. 48.
    Kholodenko BN. Four-dimensional organization of protein kinase signaling cascades: The roles of diffusion, endocytosis and molecular motors. J Exp Biol 2003; 206(Pt 12):2073–82.PubMedCrossRefGoogle Scholar
  49. 49.
    Schaefer AW, Kamiguchi H, Wong EV et al. Activation of the MAPK signal cascade by the neural cell adhesion molecule L1 requires L1 internalization. J Biol Chem 1999; 274(53):37965–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Campbell DS, Holt CE. Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones. Neuron 2003; 37(6):939–52.PubMedCrossRefGoogle Scholar
  51. 51.
    Long KE, Asou H, Snider MD et al. The role of endocytosis in regulating L1-mediated adhesion. J Biol Chem 2001; 276(2):1285–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Cohen NR, Taylor JS, Scott LB et al. Errors in corticospinal axon guidance in mice lacking the neural cell adhesion molecule L1. Curr Biol 1998; 8(1):26–3.PubMedCrossRefGoogle Scholar
  53. 53.
    Chen H, Bagri A, Zupicich JA et al. Neuropilin-2 regulates the development of selective cranial and sensory nerves and hippocampal mossy fiber projections. Neuron 2000; 25:43–56.PubMedCrossRefGoogle Scholar
  54. 54.
    Giger RJ, Cloutier JF, Sahay A et al. Neuropilin-2 is required in vivo for selective axon guidance responses to secreted semaphorins. Neuron 2000; 25:29.PubMedCrossRefGoogle Scholar
  55. 55.
    Sahay A, Molliver ME, Ginty DD et al. semaphorin 3F is critical for development of limbic system circuitry and is required in neurons for selective CNS axon guidance events. J Neurosci 2003; 23:6671–6680.PubMedGoogle Scholar
  56. 56.
    Kaprielian Z, Runko E, Imondi R. Axon guidance at the midline choice point. Dev Dyn 2001; 221(2):154–81.PubMedCrossRefGoogle Scholar
  57. 57.
    Zou Y, Stoeckli E, Chen H et al. Squeezing axons out of the gray matter: A role for slit and semaphorin proteins from midline and ventral spinal cord. Cell 2000; 102:363–375.PubMedCrossRefGoogle Scholar
  58. 58.
    Stoeckli ET, Landmesser LT. Axonin-1, Nr-CAM, and Ng-CAM play different roles in the in vivo guidance of chick commissural neurons. Neuron 1995; 14(6):1165–79.PubMedCrossRefGoogle Scholar
  59. 59.
    Pekarik V, Bourikas D, Miglino N et al. Screening for gene function in chicken embryo using RNAi and electroporation. Nat Biotechnol 2003; 21(1):93–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Tosney KW, Landmesser LT. Development of the major, pathways for neurite outgrowth in the chick hindlimb. Dev Biol 1985; 109(1):193–214.PubMedCrossRefGoogle Scholar
  61. 61.
    Ghosh A, Shatz CJ. Pathfinding and target selection by developing geniculocortical axons. J Neurosci 1992; 12(1):39–55.PubMedGoogle Scholar
  62. 62.
    Wang G, Scott SA. The_“waiting period” of sensory and motor axons in early chick hindlimb: Its role in axon pathfinding and neuronal maturation. J Neurosci 2000; 20(14):5358–66.PubMedGoogle Scholar
  63. 63.
    Tang J, Rutishauser U, Landmesser L. Polysialic acid regulates growth cone behavior during sorting of motor axons in the plexus region. Neuron 1994; 13(2):405–14.PubMedCrossRefGoogle Scholar
  64. 64.
    Huber AB, Kania A, Tran TS et al. Distinct roles for secreted semaphorin signaling in spinal motor axon guidance. Neuron 2005; 48(6):949–64.PubMedCrossRefGoogle Scholar
  65. 65.
    Perrin FE, Rathjen FG, Stoeckli ET. Distinct subpopulations of sensory afferents require F11 or axonin-1 for growth to their target layers within the spinal cord of the chick. Neuron 2001; 30(3):707–23.PubMedCrossRefGoogle Scholar
  66. 66.
    Wright DE, White FA, Gerfen RW et al. The guidance molecule semaphorin III is expressed in regions of spinal cord and periphery avoided by growing sensory axons. J Comp Neurol 1995; 361(2):321–33.PubMedCrossRefGoogle Scholar
  67. 67.
    Fu SY, Sharma K, Luo Y et al. SEMA3A regulates developing sensory projections in the chicken spinal cord. J Neurobiol 2000; 45(4):227–36.PubMedCrossRefGoogle Scholar
  68. 68.
    De Angelis E, Watkins A, Schafer M et al. Disease-associated mutations in L1 CAM interfere with ligand interactions and cell-surface expression. Hum Mol Genet 2002;11(1):1–1.PubMedCrossRefGoogle Scholar
  69. 69.
    De Angelis E, MacFarlane J, Du JS et al. Pathological missense mutations of neural cell adhesion molecule L1 affect homophilic and heterophilic binding activities. EMBO J 1999; 18(17):4744–53.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Ahmad Bechara
  • Julien Falk
  • Frédéric Moret
  • Valérie Castellani
    • 1
  1. 1.Centre de Génétique Moléculaire et Cellulaire (CGMC) UMR CNRS 5534Université Claude Bernard, Lyon1Villeurbanne cedexFrance

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