Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Wnt–Ryk signalling mediates medial–lateral retinotectal topographic mapping

Abstract

Computational modelling has suggested that at least two counteracting forces are required for establishing topographic maps. Ephrin-family proteins are required for both anterior–posterior and medial–lateral topographic mapping, but the opposing forces have not been well characterized. Wnt-family proteins are recently discovered axon guidance cues. We find that Wnt3 is expressed in a medial–lateral decreasing gradient in chick optic tectum and mouse superior colliculus. Retinal ganglion cell (RGC) axons from different dorsal–ventral positions showed graded and biphasic response to Wnt3 in a concentration-dependent manner. Wnt3 repulsion is mediated by Ryk, expressed in a ventral-to-dorsal decreasing gradient, whereas attraction of dorsal axons at lower Wnt3 concentrations is mediated by Frizzled(s). Overexpression of Wnt3 in the lateral tectum repelled the termination zones of dorsal RGC axons in vivo. Expression of a dominant-negative Ryk in dorsal RGC axons caused a medial shift of the termination zones, promoting medially directed interstitial branches and eliminating laterally directed branches. Therefore, a classical morphogen, Wnt3, acting as an axon guidance molecule, plays a role in retinotectal mapping along the medial–lateral axis, counterbalancing the medial-directed EphrinB1–EphB activity.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Wnt3 expression is graded in vertebrate midbrain and Wnt3 differentially regulated retinal axon outgrowth along the dorsal–ventral axis.
Figure 2: Graded expression of Ryk in chick and mouse retinal ganglion cells.
Figure 3: Wnt3 inhibits retinal ganglion cell axons via Ryk and stimulates retinal ganglion cell axons via Frizzled(s).
Figure 4: Termination zone of abnormalities in tectum ectopically expressing Wnt3.
Figure 5: Ryk is required for normal medial–lateral patterning of RGC axon termination.
Figure 6: Model of two counterbalancing forces for medial–lateral map formation.

References

  1. Prestige, M. C. & Willshaw, D. J. On a role for competition in the formation of patterned neural connexions. Proc. R. Soc. Lond. B 190, 77– 98 (1975)

    Article  ADS  CAS  Google Scholar 

  2. Gierer, A. Model for the retino-tectal projection. Proc. R. Soc. Lond. B 218, 77– 93 (1983)

    Article  ADS  CAS  Google Scholar 

  3. Fraser, S. E. & Hunt, R. K. Retinotectal specificity: models and experiments in search of a mapping function. Annu. Rev. Neurosci. 3, 319– 352 (1980)

    Article  CAS  Google Scholar 

  4. Fraser, S. E. & Perkel, D. H. Competitive and positional cues in the patterning of nerve connections. J. Neurobiol. 21, 51– 72 (1990)

    Article  CAS  Google Scholar 

  5. Flanagan, J. G. & Vanderhaeghen, P. The ephrins and Eph receptors in neural development. Annu. Rev. Neurosci. 21, 309– 345 (1998)

    Article  CAS  Google Scholar 

  6. Frisen, J. et al. Ephrin-A5 (AL-1/RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system. Neuron 20, 235– 243 (1998)

    Article  CAS  Google Scholar 

  7. Feldheim, D. A. et al. Topographic guidance labels in a sensory projection to the forebrain. Neuron 21, 1303– 1313 (1998)

    Article  CAS  Google Scholar 

  8. Feldheim, D. A. et al. Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping. Neuron 25, 563– 574 (2000)

    Article  CAS  Google Scholar 

  9. Mann, F., Ray, S., Harris, W. & Holt, C. Topographic mapping in dorsoventral axis of the Xenopus retinotectal system depends on signalling through ephrin-B ligands. Neuron 35, 461– 473 (2002)

    Article  CAS  Google Scholar 

  10. Hindges, R., McLaughlin, T., Genoud, N., Henkemeyer, M. & O'Leary, D. D. EphB forward signalling controls directional branch extension and arborization required for dorsal-ventral retinotopic mapping. Neuron 35, 475– 487 (2002)

    Article  CAS  Google Scholar 

  11. Lyuksyutova, A. I. et al. Anterior-posterior guidance of commissural axons by Wnt-frizzled signalling. Science 302, 1984– 1988 (2003)

    Article  ADS  CAS  Google Scholar 

  12. Drescher, U. 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 82, 359– 370 (1995)

    Article  CAS  Google Scholar 

  13. Smolich, B. D., McMahon, J. A., McMahon, A. P. & Papkoff, J. Wnt family proteins are secreted and associated with the cell surface. Mol. Biol. Cell 4, 1267– 1275 (1993)

    Article  CAS  Google Scholar 

  14. Willert, K. et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448– 452 (2003)

    Article  ADS  CAS  Google Scholar 

  15. Yoshikawa, S., McKinnon, R. D., Kokel, M. & Thomas, J. B. Wnt-mediated axon guidance via the Drosophila Derailed receptor. Nature 422, 583– 588 (2003)

    Article  ADS  CAS  Google Scholar 

  16. Liu, Y. et al. Ryk-mediated Wnt repulsion regulates posterior-directed growth of corticospinal tract. Nature Neurosci. 8, 1151– 1159 (2005)

    Article  CAS  Google Scholar 

  17. Hovens, C. M. et al. RYK, a receptor tyrosine kinase-related molecule with unusual kinase domain motifs. Proc. Natl Acad. Sci. USA 89, 11818– 11822 (1992)

    Article  ADS  CAS  Google Scholar 

  18. Dann, C. E. et al. Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature 412, 86– 90 (2001)

    Article  ADS  CAS  Google Scholar 

  19. Hsieh, J. C., Rattner, A., Smallwood, P. M. & Nathans, J. Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. Proc. Natl Acad. Sci. USA 96, 3546– 3551 (1999)

    Article  ADS  CAS  Google Scholar 

  20. Patthy, L. The WIF module. Trends Biochem. Sci. 25, 12– 13 (2000)

    Article  CAS  Google Scholar 

  21. Mey, J. & Thanos, S. Development of the visual system of the chick. I. Cell differentiation and histogenesis. Brain Res. Rev. 32, 343– 379 (2000)

    Article  CAS  Google Scholar 

  22. Liu, P. et al. Requirement for Wnt3 in vertebrate axis formation. Nature Genet. 22, 361– 365 (1999)

    Article  CAS  Google Scholar 

  23. Halford, M. M. et al. Ryk-deficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk. Nature Genet. 25, 414– 418 (2000)

    Article  CAS  Google Scholar 

  24. Inoue, T. et al. C. elegans LIN-18 is a Ryk ortholog and functions in parallel to LIN-17/Frizzled in Wnt signalling. Cell 118, 795– 806 (2004)

    Article  CAS  Google Scholar 

  25. Hansen, M. J., Dallal, G. E. & Flanagan, J. G. Retinal axon response to ephrin-as shows a graded, concentration-dependent transition from growth promotion to inhibition. Neuron 42, 717– 730 (2004)

    Article  CAS  Google Scholar 

  26. McLaughlin, T., Hindges, R. & O'Leary, D. D. Regulation of axial patterning of the retina and its topographic mapping in the brain. Curr. Opin. Neurobiol. 13, 57– 69 (2003)

    Article  CAS  Google Scholar 

  27. Flanagan, J. G. & Leder, P. The kit ligand: a cell surface molecule altered in steel mutant fibroblasts. Cell 63, 185– 194 (1990)

    Article  CAS  Google Scholar 

  28. Cheng, H. J. & Flanagan, J. G. Identification and cloning of ELF-1, a developmentally expressed ligand for the Mek4 and Sek receptor tyrosine kinases. Cell 79, 157– 168 (1994)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Alfred Sloan Foundation, the Schweppe Foundation and NINDS. We thank F. Polleux for the pCIG2 vector (CMV-enhanced β-actin promoter with IRES GFP marker) and A. G. Fenstermaker for critical reading of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yimin Zou.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Sense controls for in situ (PDF 126 kb)

Supplementary Figure 2

a) the relative outgrowth of RGC axons b) Wnt3 activity on RGC axons (PDF 45 kb)

Supplementary Figure 3

Supplementary Figure 3 nature04334-s3.pdf Localization of Ryk protein. (PDF 1408 kb)

Supplementary Figure 4

Ryk is a high-affinity Wnt receptor. (PDF 133 kb)

Supplementary Figure 5

a) Electroporation of a Wnt3 expression construct at E7, traced RGC axon termini with DiI injection at E13, and harvested tecta on E14. b) The normal medial–lateral gradient of ephrinB1 was not altered in the chick tectum electroporated with Wnt3. (PDF 752 kb)

Supplementary Figure 6

a) Generation of a dominant-negative form of Ryk and its expression in chick RGCs. e) Normal graded expression patterns of cell differentiation markers, such as EphrinB1 and EphB2 were not affected. (PDF 797 kb)

Supplementary Methods

Additional description of the methods used in this study. (DOC 52 kb)

Supplementary Table

Additional data to accompany the results, including Standard Error values. (XLS 35 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schmitt, A., Shi, J., Wolf, A. et al. Wnt–Ryk signalling mediates medial–lateral retinotectal topographic mapping. Nature 439, 31–37 (2006). https://doi.org/10.1038/nature04334

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04334

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing