Skip to main content
SpringerLink
Log in

Axonal Guidance

  • Chapter
  • First Online:
Neurodevelopmental Pediatrics

  • 1510 Accesses

Abstract

An essential stage in nervous system development is elaboration of axons from nascent neurons and guidance of these axons toward their final targets, often via intermediate targets. The processes underlying axonal guidance are complex and involve short- and long-range attractive and/or repulsive cues. Furthermore, axonal guidance requires the dynamic interplay of cytoskeletal reorganization via cycles of actin polymerization and depolymerization as well as the developmentally regulated expression of membrane-bound receptors of axonal growth cones. Signaling-mediated downstream of growth cone receptors relies on secreted or membrane-tethered extracellular cues (or ligands) resulting in chemoattraction or chemorepulsion of the growth cone toward or away from these cues, respectively. To date, several neurological diseases, including neurodevelopmental disorders, have been attributed to mutations or dysregulation of specific genes encoding growth cone receptors, ligands, or extracellular cues required for axonal guidance.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Tessier-Lavigne M, Goodman CS. The molecular biology of axon guidance. Science. 1996;274(5290):1123–33.

    Article  CAS  Google Scholar 

  2. Raper J, Mason C. Cellular strategies of axonal pathfinding. Cold Spring Harb Perspect Biol. 2010;2(9):a001933.

    Article  Google Scholar 

  3. 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.

    Article  CAS  Google Scholar 

  4. Höpker VH, Shewan D, Tessier-Lavigne M, Poo M-M, Holt C. Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1. Nature. 1999;401(6748):69–73.

    Article  Google Scholar 

  5. Kaplan A, Kent CB, Charron F, Fournier AE. Switching responses: spatial and temporal regulators of axon guidance. Mol Neurobiol. 2014;49(2):1077–86.

    Article  CAS  Google Scholar 

  6. Seeger M, Tear G, Ferres-Marco D, Goodman CS. Mutations affecting growth cone guidance in drosophila: genes necessary for guidance toward or away from the midline. Neuron. 1993;10(3):409–26.

    Article  CAS  Google Scholar 

  7. Kidd T, Bland KS, Goodman CS. Slit is the midline repellent for the robo receptor in drosophila. Cell. 1999;96(6):785–94.

    Article  CAS  Google Scholar 

  8. Long H, Sabatier C, Ma L, Plump A, Yuan W, Ornitz DM, et al. Conserved roles for slit and Robo proteins in midline commissural axon guidance. Neuron. 2004;42(2):213–23.

    Article  CAS  Google Scholar 

  9. Tear G, Harris R, Sutaria S, Kilomanski K, Goodman CS, Seeger MA. Commissureless controls growth cone guidance across the CNS midline in drosophila and encodes a novel membrane protein. Neuron. 1996;16(3):501–14.

    Article  CAS  Google Scholar 

  10. Keleman K, Rajagopalan S, Cleppien D, Teis D, Paiha K, Huber LA, et al. Comm sorts robo to control axon guidance at the drosophila midline. Cell. 2002;110(4):415–27.

    Article  CAS  Google Scholar 

  11. Marillat V, Sabatier C, Failli V, Matsunaga E, Sotelo C, Tessier-Lavigne M, Chédotal A. The slit receptor Rig-1/Robo3 controls midline crossing by hindbrain precerebellar neurons and axons. Neuron. 2004;43(1):69–79.

    Article  CAS  Google Scholar 

  12. Sabatier C, Plump AS, Ma L, Brose K, Tamada A, Murakami F, et al. The divergent Robo family protein rig-1/Robo3 is a negative regulator of slit responsiveness required for midline crossing by commissural axons. Cell. 2004;117(2):157–69.

    Article  CAS  Google Scholar 

  13. Zelina P, Blockus H, Zagar Y, Péres A, Friocourt F, Wu Z, et al. Signaling switch of the axon guidance receptor Robo3 during vertebrate evolution. Neuron. 2014;84(6):1258–72.

    Article  CAS  Google Scholar 

  14. Yuan S-SF, Cox LA, Dasika GK, Eva Y-HL. Cloning and functional studies of a novel gene aberrantly expressed in RB-deficient embryos. Dev Biol. 1999;207(1):62–75.

    Article  CAS  Google Scholar 

  15. Chen Z, Gore BB, Long H, Ma L, Tessier-Lavigne M. Alternative splicing of the Robo3 axon guidance receptor governs the midline switch from attraction to repulsion. Neuron. 2008;58(3):325–32.

    Article  CAS  Google Scholar 

  16. Chédotal A. Roles of axon guidance molecules in neuronal wiring in the developing spinal cord. Nat Rev Neurosci. 2019;20(7):380–96.

    Article  Google Scholar 

  17. Alto LT, Terman JR. Semaphorins and their signaling mechanisms. In: Semaphorin signaling. Springer; 2017. p. 1–25.

    Google Scholar 

  18. Kolodkin AL, Matthes DJ, O’Connor TP, Patel NH, Admon A, Bentley D, Goodman CS. Fasciclin IV: sequence, expression, and function during growth cone guidance in the grasshopper embryo. Neuron. 1992;9(5):831–45.

    Article  CAS  Google Scholar 

  19. Kolodkin AL, Matthes DJ, Goodman CS. The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell. 1993;75(7):1389–99.

    Article  CAS  Google Scholar 

  20. 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.

    Article  CAS  Google Scholar 

  21. Stoeckli ET. Understanding axon guidance: are we nearly there yet? Development. 2018;145(10):dev151415.

    Article  Google Scholar 

  22. Zou Y, Stoeckli E, Chen H, Tessier-Lavigne M. Squeezing axons out of the gray matter: a role for slit and semaphorin proteins from midline and ventral spinal cord. Cell. 2000;102(3):363–75.

    Article  CAS  Google Scholar 

  23. Hernandez-Enriquez B, Wu Z, Martinez E, Olsen O, Kaprielian Z, Maness PF, et al. Floor plate-derived neuropilin-2 functions as a secreted semaphorin sink to facilitate commissural axon midline crossing. Genes Dev. 2015;29(24):2617–32.

    Article  Google Scholar 

  24. Kullander K, Croll SD, Zimmer M, Pan L, McClain J, Hughes V, et al. Ephrin-B3 is the midline barrier that prevents corticospinal tract axons from recrossing, allowing for unilateral motor control. Genes Dev. 2001;15(7):877–88.

    Article  CAS  Google Scholar 

  25. Yokoyama N, Romero MI, Cowan CA, Galvan P, Helmbacher F, Charnay P, et al. Forward signaling mediated by ephrin-B3 prevents contralateral corticospinal axons from recrossing the spinal cord midline. Neuron. 2001;29(1):85–97.

    Article  CAS  Google Scholar 

  26. Walter J, Henke-Fahle S, Bonhoeffer F. Avoidance of posterior tectal membranes by temporal retinal axons. Development. 1987;101(4):909–13.

    Article  CAS  Google Scholar 

  27. Walter J, Kern-Veits B, Huf J, Stolze B, Bonhoeffer F. Recognition of position-specific properties of tectal cell membranes by retinal axons in vitro. Development. 1987;101(4):685–96.

    Article  CAS  Google Scholar 

  28. Cheng H-J, Nakamoto M, Bergemann AD, Flanagan JG. Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map. Cell. 1995;82(3):371–81.

    Article  CAS  Google Scholar 

  29. Drescher U, Kremoser C, Handwerker C, Löschinger J, Noda M, Bonhoeffer F. 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):359–70.

    Article  CAS  Google Scholar 

  30. Triplett JW, Feldheim DA. Eph and ephrin signaling in the formation of topographic maps. Paper presented at the Seminars in cell & developmental biology, vol. 23; 2012. p. 7–15.

    Google Scholar 

  31. Brown A, Yates PA, Burrola P, Ortuño D, Vaidya A, Jessell TM, et al. Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling. Cell. 2000;102(1):77–88.

    Article  CAS  Google Scholar 

  32. Feldheim DA, Kim Y-I, Bergemann AD, Frisén J, Barbacid M, Flanagan JG. Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping. Neuron. 2000;25(3):563–74.

    Article  CAS  Google Scholar 

  33. Frisén J, Yates PA, McLaughlin T, Friedman GC, O'Leary DD, Barbacid M. Ephrin-A5 (AL-1/RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system. Neuron. 1998;20(2):235–43.

    Article  Google Scholar 

  34. Klein R. Eph/ephrin signalling during development Development. 2012;139(22):4105–9.

    CAS  Google Scholar 

  35. Kennedy TE, Serafini T, de la Torre J, Tessier-Lavigne M. Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Cell. 1994;78(3):425–35.

    Article  CAS  Google Scholar 

  36. Serafini T, Kennedy TE, Gaiko MJ, Mirzayan C, Jessell TM, Tessier-Lavigne M. The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell. 1994;78(3):409–24.

    Article  CAS  Google Scholar 

  37. Serafini T, Colamarino SA, Leonardo ED, Wang H, Beddington R, Skarnes WC, Tessier-Lavigne M. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell. 1996;87(6):1001–14.

    Article  CAS  Google Scholar 

  38. Dominici C, Moreno-Bravo JA, Puiggros SR, Rappeneau Q, Rama N, Vieugue P, et al. Floor-plate-derived netrin-1 is dispensable for commissural axon guidance. Nature. 2017;545(7654):350–4.

    Article  CAS  Google Scholar 

  39. Varadarajan SG, Kong JH, Phan KD, Kao T-J, Panaitof SC, Cardin J, et al. Netrin1 produced by neural progenitors, not floor plate cells, is required for axon guidance in the spinal cord. Neuron. 2017;94(4):790–9. e793

    Article  CAS  Google Scholar 

  40. Colamarino SA, Tessier-Lavigne M. The axonal chemoattractant netrin-1 is also a chemorepellent for trochlear motor axons. Cell. 1995;81(4):621–9.

    Article  CAS  Google Scholar 

  41. Gao X, Metzger U, Panza P, Mahalwar P, Alsheimer S, Geiger H, et al. A floor-plate extracellular protein-protein interaction screen identifies Draxin as a secreted Netrin-1 antagonist. Cell Rep. 2015;12(4):694–708.

    Article  CAS  Google Scholar 

  42. Islam SM, Shinmyo Y, Okafuji T, Su Y, Naser IB, Ahmed G, et al. Draxin, a repulsive guidance protein for spinal cord and forebrain commissures. Science. 2009;323(5912):388–93.

    Article  CAS  Google Scholar 

  43. Jain S, Welshhans K. Netrin-1 induces local translation of down syndrome cell adhesion molecule in axonal growth cones. Dev Neurobiol. 2016;76(7):799–816.

    Article  CAS  Google Scholar 

  44. Bashaw GJ, Klein R. Signaling from axon guidance receptors. Cold Spring Harb Perspect Biol. 2010;2(5):a001941.

    Article  Google Scholar 

  45. Hattori M, Osterfield M, Flanagan JG. Regulated cleavage of a contact-mediated axon repellent. Science. 2000;289(5483):1360–5.

    Article  CAS  Google Scholar 

  46. Parra LM, Zou Y. Sonic hedgehog induces response of commissural axons to Semaphorin repulsion during midline crossing. Nat Neurosci. 2010;13(1):29–35.

    Article  CAS  Google Scholar 

  47. Song H-J, Ming G-L, He Z, Lehmann M, McKerracher L, Tessier-Lavigne M, Poo M-M. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science. 1998;281(5382):1515–8.

    Article  CAS  Google Scholar 

  48. Shewan D, Dwivedy A, Anderson R, Holt C. Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathway. Nat Neurosci. 2002;5(10):955–62.

    Article  CAS  Google Scholar 

  49. Huber AB, Kolodkin AL, Ginty DD, Cloutier J-F. Signaling at the growth cone: ligand-receptor complexes and the control of axon growth and guidance. Annu Rev Neurosci. 2003;26(1):509–63.

    Article  CAS  Google Scholar 

  50. Causeret F, Hidalgo-Sanchez M, Fort P, Backer S, Popoff MR, Gauthier-Rouviere C, Bloch-Gallego E. Distinct roles of Rac1/Cdc42 and rho/rock for axon outgrowth and nucleokinesis of precerebellar neurons toward netrin 1. Development. 2004;131(12):2841–52. https://doi.org/10.1242/dev.01162.

    Article  CAS  Google Scholar 

  51. Nishiyama M, Hoshino A, Tsai L, Henley JR, Goshima Y, Tessier-Lavigne M, et al. Cyclic AMP/GMP-dependent modulation of Ca2+ channels sets the polarity of nerve growth-cone turning. Nature. 2003;423(6943):990–5. https://doi.org/10.1038/nature01751.

    Article  CAS  Google Scholar 

  52. Zhou Y, Gunput R-AF, Pasterkamp RJ. Semaphorin signaling: progress made and promises ahead. Trends Biochem Sci. 2008;33(4):161–70.

    Article  CAS  Google Scholar 

  53. Nugent AA, Kolpak AL, Engle EC. Human disorders of axon guidance. Curr Opin Neurobiol. 2012;22(5):837–43.

    Article  CAS  Google Scholar 

  54. Jen JC, Chan W-M, Bosley TM, Wan J, Carr JR, Rüb U, et al. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science. 2004;304(5676):1509–13.

    Article  CAS  Google Scholar 

  55. Accogli A, Calabretta S, St-Onge J, Boudrahem-Addour N, Dionne-Laporte A, Joset P, et al. De novo pathogenic variants in N-cadherin cause a syndromic neurodevelopmental disorder with corpus callosum, axon, cardiac, ocular, and genital defects. Am J Hum Genet. 2019;105(4):854–68.

    Article  CAS  Google Scholar 

  56. Meneret A, Depienne C, Riant F, Trouillard O, Bouteiller D, Cincotta M, et al. Congenital mirror movements: mutational analysis of RAD51 and DCC in 26 cases. Neurology. 2014;82(22):1999–2002. https://doi.org/10.1212/WNL.0000000000000477.

    Article  CAS  Google Scholar 

  57. Van Battum EY, Brignani S, Pasterkamp RJ. Axon guidance proteins in neurological disorders. The Lancet Neurology. 2015;14(5):532–46.

    Article  Google Scholar 

  58. Giger RJ, Hollis ER, Tuszynski MH. Guidance molecules in axon regeneration. Cold Spring Harb Perspect Biol. 2010;2(7):a001867.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

    Mikaela Nevin, Janine Gallego & David D. Eisenstat

  2. Neuroscience Program, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

    Janine Gallego

  3. Faculty of Nursing, University of Alberta, Edmonton, AB, Canada

    Janine Gallego

  4. Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

    David D. Eisenstat

  5. Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

    David D. Eisenstat

  6. Department of Paediatrics, Murdoch Children’s Research Institute, University of Melbourne, Parkville, VIC, Australia

    David D. Eisenstat

Authors
  1. Mikaela Nevin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Janine Gallego
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David D. Eisenstat
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David D. Eisenstat .

Editor information

Editors and Affiliations

  1. Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia

    David D. Eisenstat

  2. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

    Dan Goldowitz

  3. Department of Pediatrics and School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada

    Tim F. Oberlander

  4. Department of Pediatrics, University of Alberta, Edmonton, AB, Canada

    Jerome Y. Yager

Rights and permissions

Reprints and permissions

Copyright information

© 2023 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Nevin, M., Gallego, J., Eisenstat, D.D. (2023). Axonal Guidance. In: Eisenstat, D.D., Goldowitz, D., Oberlander, T.F., Yager, J.Y. (eds) Neurodevelopmental Pediatrics. Springer, Cham. https://doi.org/10.1007/978-3-031-20792-1_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-20792-1_6

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-031-20791-4

  • Online ISBN: 978-3-031-20792-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation