The Hedgehog, TGF-β/BMP and Wnt Families of Morphogens in Axon Guidance

  • Frédéric Charron
  • Marc Tessier-Lavigne
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 621)


During embryonic development, morphogens act as graded positional cues to dictate cell fate specification and tissue patterning. Recent findings indicate that morphogen gradients also serve to guide axonal pathfinding during development of the nervous system. These findings challenge our previous notions about morphogens and axon guidance molecules and suggest that these proteins, rather than having sharply divergent functions, act more globally to provide graded positional information that can be interpreted by responding cells either to specify cell fate or to direct axonal pathfinding. This chapter presents the roles identified for members of three prominent morphogen families—the Hedgehog, Wnt and TGF-β/BMP families—in axon guidance, and discusses potential implications for the molecular mechanisms underlying their guidance functions.


Growth Cone Axon Guidance Anterior Commissure Planar Cell Polarity Floor Plate 
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.
    Dickson BJ. Molecular mechanisms of axon guidance. Science 2002; 298(5600):1959–1964.PubMedCrossRefGoogle Scholar
  2. 2.
    Tessier-Lavigne M, Goodman CS. The molecular biology of axon guidance. Science 1996; 274(5290):1123–1133.PubMedCrossRefGoogle Scholar
  3. 3.
    Teleman AA, Strigini M, Cohen SM. Shaping morphogen gradients. Cell 2001; 105(5):559–562.PubMedCrossRefGoogle Scholar
  4. 4.
    Gurdon JB, Dyson S, St Johnston D. Cells’ perception of position in a concentration gradient. Cell 1998; 95(2):159–162.PubMedCrossRefGoogle Scholar
  5. 5.
    Chen Y, Schier AF. The zebrafish Nodal signal Squint functions as a morphogen. Nature 2001; 411(6837):607–610.PubMedCrossRefGoogle Scholar
  6. 6.
    Briscoe J, Chen Y, Jessell TM et al. A hedgehog-insensitive form of patched provides evidence for direct long-range morphogen activity of sonic hedgehog in the neural tube. Mol Cell 2001; 7(6):1279–1291.PubMedCrossRefGoogle Scholar
  7. 7.
    Jessell TM. Neuronal specification in the spinal cord: Inductive signals and transcriptional codes. Nat Rev Genet 2000; 1(1):20–29.PubMedCrossRefGoogle Scholar
  8. 8.
    Ingham PW, McMahon AP. Hedgehog signaling in animal development: Paradigms and principles. Genes Dev 2001; 15(23):3059–3087.PubMedCrossRefGoogle Scholar
  9. 9.
    Marti E, Bovolenta P. Sonic hedgehog in CNS development: One signal, multiple outputs. Trends Neurosci 2002; 25(2):89–96.PubMedCrossRefGoogle Scholar
  10. 10.
    Roelink H, Porter JA, Chiang C et al. Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis. Cell 1995; 81(3):445–455.PubMedCrossRefGoogle Scholar
  11. 11.
    Lum L, Beachy PA. The Hedgehog response network: Sensors, switches, and routers. Science 2004; 304(5678):1755–1759.PubMedCrossRefGoogle Scholar
  12. 12.
    Lee KJ, Jessell TM. The specification of dorsal cell fates in the vertebrate central nervous system. Annu Rev Neurosci 1999; 22:261–294.PubMedCrossRefGoogle Scholar
  13. 13.
    Lee KJ, Mendelsohn M, Jessell TM. Neuronal patterning by BMPs: A requirement for GDF7 in the generation of a discrete class of commissural interneurons in the mouse spinal cord. Genes Dev 1998; 12(21):3394–3407.PubMedCrossRefGoogle Scholar
  14. 14.
    Muroyama Y, Fujihara M, Ikeya M et al. Wnt signaling plays an essential role in neuronal specification of the dorsal spinal cord.Genes Dev 2002; 16 (5):548–553.PubMedCrossRefGoogle Scholar
  15. 15.
    Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 2004. 303(5663):1483–1487.PubMedCrossRefGoogle Scholar
  16. 16.
    Strutt D. Frizzled signalling and cell polarisation in Drosophila and vertebrates. Development 2003; 130(19):4501–4513.PubMedCrossRefGoogle Scholar
  17. 17.
    Colamarino SA, Tessier-Lavigne M. The role of the floor plate in axon guidance. Annu Rev Neurosci 1995; 18:497–529.PubMedCrossRefGoogle Scholar
  18. 18.
    Kennedy TE, Serafini T, de la Torre JR et al. Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Cell 1994; 78(3):425–435.PubMedCrossRefGoogle Scholar
  19. 19.
    Placzek M, Tessier-Lavigne M, Jessell T et al. Orientation of commissural axons in vitro in response to a floor plate-derived chemoattractant. Development 1990; 110(1):19–30.PubMedGoogle Scholar
  20. 20.
    Serafini T, Colamarino SA, Leonardo ED et al. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 1996; 87(6):1001–1014.PubMedCrossRefGoogle Scholar
  21. 21.
    Serafini T, Kennedy TE, Galko MJ et al. The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell 1994; 78(3):409–424.PubMedCrossRefGoogle Scholar
  22. 22.
    Tessier-Lavigne M, Placzek M, Lumsden AG et al. Chemotropic guidance of developing axons in the mammalian central nervous system. Nature 1988; 336(6201):775–778.PubMedCrossRefGoogle Scholar
  23. 23.
    Fazeli A, Dickinson SL, Hermiston ML et al. Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene. Nature 1997; 386(6627):796–804.PubMedCrossRefGoogle Scholar
  24. 24.
    Charron F, Stein E, Jeong J et al. The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance. Cell 2003; 113(1):11–23.PubMedCrossRefGoogle Scholar
  25. 25.
    Bourikas D, Pekarik V, Baeriswyl T et al. Sonic hedgehog guides commissural axons along the longitudinal axis of the spinal cord. Nat Neurosci 2005.Google Scholar
  26. 26.
    Torres M, Gomez-Pardo E, Gruss P. Pax2 contributes to inner ear patterning and optic nerve trajectory. Development 1996; 122(11):3381–3391.PubMedGoogle Scholar
  27. 27.
    Trousse F, Marti E, Gruss P et al. Control of retinal ganglion cell axon growth: A new role for Sonic hedgehog. Development 2001; 128(20):3927–3936.PubMedGoogle Scholar
  28. 28.
    Song HJ, Ming GL, Poo MM. cAMP-induced switching in turning direction of nerve growth cones. Nature 1997; 388(6630):275–279.PubMedGoogle Scholar
  29. 29.
    Song H, Ming G, He Z et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 1998; 281(5382):1515–1518.PubMedCrossRefGoogle Scholar
  30. 30.
    Song HJ, Poo MM. Signal transduction underlying growth cone guidance by diffusible factors. Curr Opin Neurobiol 1999; 9(3):355–363.PubMedCrossRefGoogle Scholar
  31. 31.
    Hopker VH, Shewan D, Tessier-Lavigne M et al. Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1. Nature 1999; 401(6748):69–73.PubMedCrossRefGoogle Scholar
  32. 32.
    Augsburger A, Schuchardt A, Hoskins S et al. BMPs as mediators of roof plate repulsion of commissural neurons. Neuron 1999; 24(1):127–141.PubMedCrossRefGoogle Scholar
  33. 33.
    Butler SJ, Dodd J. A role for BMP heterodimers in roof plate-mediated repulsion of commissural axons. Neuron 2003; 38(3):389–401.PubMedCrossRefGoogle Scholar
  34. 34.
    Lee YS, Chuong CM. Activation of protein kinase A is a pivotal step involved in both BMP-2-and cyclic AMP-induced chondrogenesis. J Cell Physiol 1997; 170(2):153–165.PubMedCrossRefGoogle Scholar
  35. 35.
    Foletta VC, Lim MA, Soosairajah J et al. Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. J Cell Biol 2003; 162(6):1089–1098.PubMedCrossRefGoogle Scholar
  36. 36.
    Halstead J, Kemp K, Ignotz RA. Evidence for involvement of phosphatidylcholine-phospholipase C and protein kinase C in transforming growth factor-beta signaling. J Biol Chem 1995; 270(23):13600–13603.PubMedCrossRefGoogle Scholar
  37. 37.
    Choi SE, Choi EY, Kim PH et al. Involvement of protein kinase C and rho GTPase in the nuclear signalling pathway by transforming growth factor-betal in rat-2 fibroblast cells. Cell Signal 1999; 11(1):71–76.PubMedCrossRefGoogle Scholar
  38. 38.
    Colavita A, Culotti JG. Suppressors of ectopic UNC-5 growth cone steering identify eight genes involved in axon giidance in Caenorhabditis elegans Dev Biol 1998: 194(1):72–85.PubMedCrossRefGoogle Scholar
  39. 39.
    Colavita A, Krishna S, Zheng H et al. Pioneer axon guidance by UNC-129, a C. elegans TGF-beta. Science 1998; 281(5377):706–709.PubMedCrossRefGoogle Scholar
  40. 40.
    Hedgecock EM, Culotti JG, Hall DH. The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans. Neuron 1990; 4(1):61–85.PubMedCrossRefGoogle Scholar
  41. 41.
    Nash B, Colavita A, Zheng H et al. The forkhead transcription factor UNC-130 is required for the graded spatial expression of the UNC-129 TGF-beta guidance factor in C. elegans. Genes Dev 2000; 14(19):2486–2500.PubMedCrossRefGoogle Scholar
  42. 42.
    Hall AC, Lucas FR, Salinas PC. Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Cell 2000; 100(5):525–535.PubMedCrossRefGoogle Scholar
  43. 43.
    Callahan CA, Muralidhar MG, Lundgren SE et al. Control of neuronal pathway selection by a Drosophila receptor protein-tyrosine kinase family member. Nature 1995; 376(6536):171–174.PubMedCrossRefGoogle Scholar
  44. 44.
    Bonkowsky JL, Yoshikawa S, O’Keefe DD et al. Axon routing across the midline controlled by the Drosophila Derailed receptor. Nature 1999; 402(6761):540–544.PubMedCrossRefGoogle Scholar
  45. 45.
    Yoshikawa S, McKinnon RD, Kokel M et al. Wnt-mediated axon guidance via the Drosophila Derailed receptor. Nature 2003; 422(6932):583–588.PubMedCrossRefGoogle Scholar
  46. 46.
    Patthy L. The WIF module. Trends Biochem Sci 2000; 25(1):12–13.PubMedCrossRefGoogle Scholar
  47. 47.
    Lyuksyutova AI, Lu CC, Milanesio N et al. Anterior-posterior guidance of commissural axons by Wnt-frizzled signaling. Science 2003; 302(5652):1984–1988.PubMedCrossRefGoogle Scholar
  48. 48.
    Wang Y, Thekdi N, Smallwood PM et al. Frizzled-3 is required for the development of major fiber tracts in the rostral CNS. J Neurosci 2002; 22(19):8563–8573.PubMedGoogle Scholar
  49. 49.
    He X, Semenov M, Tamai K et al. LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: Arrows point the way. Development 2004; 131(8):1663–1677.PubMedCrossRefGoogle Scholar
  50. 50.
    Liu Y, Shi J, Lu CC et al. Ryk-mediated Wnt repulsion regulates posterior-directed growth of corticospinal tract. Nat Neurosci 2005; 8(9):1151–1159.PubMedCrossRefGoogle Scholar
  51. 51.
    Cheng HJ, Nakamoto M, Bergemann AD et al. Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map, Cell 1995; 82(3):371–381.PubMedCrossRefGoogle Scholar
  52. 52.
    Drescher U, Kremoser C, Handwerker C et al. In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases. Cell 1995; 82(3):359–370.PubMedCrossRefGoogle Scholar
  53. 53.
    Hindges R, McLaughlin T, Genoud N et al. EphB forward signaling controls directional branch extension and arborization required for dorsal-ventral retinotopic mapping. Neuron 2002; 35(3):475–487.PubMedCrossRefGoogle Scholar
  54. 54.
    Mann F, Ray S, Harris W et al. Topographic mapping in dorsoventral axis of the Xenopus retinotectal system depends on signaling through ephrin-B ligands. Neuron 2002; 35(3):461–473.PubMedCrossRefGoogle Scholar
  55. 55.
    Schmitt AM, Shi J, Wolf AM et al. Wnt-Ryk signalling mediates medial-lateral retinotectal topographic mapping. Nature 2006; 439(7072):31–37.PubMedGoogle Scholar
  56. 56.
    Kuhl M, Sheldahl LC, Park M et al. The Wnt/Ca2+ pathway: A new vertebrate Wnt signaling pathway takes shape. Trends Genet 2000; 16(7):279–283.PubMedCrossRefGoogle Scholar
  57. 57.
    Lu X, Borchers AG, Jolicoeur C et al. PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature 2004; 430(6995):93–98.PubMedCrossRefGoogle Scholar
  58. 58.
    Winberg ML, Tamagnone L, Bai J et al. The transmembrane protein Off-track associates with Plexins and functions downstream of Semaphorin signaling during axon guidance. Neuron 2001; 32(1):53–62.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Frédéric Charron
    • 1
  • Marc Tessier-Lavigne
  1. 1.Molecular Biology of Neural DevelopmentInstitut de Recherches Cliniques de Montréal (IRCM)MontrealCanada

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