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The Journal of Neuroscience, May 24, 2006, 26(21):5840-5848; doi:10.1523/JNEUROSCI.1175-06.2006

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Development/Plasticity/Repair
The Wnt Receptor Ryk Is Required for Wnt5a-Mediated Axon Guidance on the Contralateral Side of the Corpus Callosum

Thomas R. Keeble,¹ Michael M. Halford,² Clare Seaman,¹ Nigel Kee,¹ Maria Macheda,⁴ Richard B. Anderson,³ Steven A. Stacker,⁴ and Helen M. Cooper¹

¹The Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia, ²Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, ³Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Victoria 3010, Australia, and ⁴Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia

Correspondence should be addressed to Dr. Helen Cooper, The Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia. Email: h.cooper{at}uq.edu.au

Ryk (receptor related to tyrosine kinase) has been shown to be a novel Wnt receptor in both Caenorhabditis elegans and Drosophila melanogaster. Recently, Ryk–Wnt interactions were shown to guide corticospinal axons down the embryonic mouse spinal cord. Here we show that, in Ryk-deficient mice, cortical axons project aberrantly across the major forebrain commissure, the corpus callosum. Many mouse mutants have been described in which loss-of-function mutations result in the inability of callosal axons to cross the midline, thereby forming Probst bundles on the ipsilateral side. In contrast, loss of Ryk does not interfere with the ability of callosal axons to cross the midline but impedes their escape from the midline into the contralateral side. Therefore, Ryk^–/– mice display a novel callosal guidance phenotype. We also show that Wnt5a acts as a chemorepulsive ligand for Ryk, driving callosal axons toward the contralateral hemisphere after crossing the midline. In addition, whereas callosal axons do cross the midline in Ryk^–/– embryos, they are defasciculated on the ipsilateral side, indicating that Ryk also promotes fasciculation of axons before midline crossing. In summary, this study expands the emerging role for Wnts in axon guidance and identifies Ryk as a key guidance receptor in the establishment of the corpus callosum. Our analysis of Ryk function further advances our understanding of the molecular mechanisms underlying the formation of this important commissure.

Key words: axon guidance; corpus callosum; Ryk receptor; loss-of-function; Wnt5a; chemorepulsion

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Received Oct. 28, 2005; revised April 10, 2006; accepted April 11, 2006.

Correspondence should be addressed to Dr. Helen Cooper, The Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia. Email: h.cooper{at}uq.edu.au

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