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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.

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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.

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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.

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Correspondence to Yimin Zou.

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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)

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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

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