title: The Wnt receptor Ryk is required for Wnt5a-mediated axon guidance on the contralateral side of the corpus callosum.
abstract: 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.
authors.affiliation: The Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Keeble
authors.forename: Michael M
authors.initials: MM
authors.lastname: Halford
authors.forename: Clare
authors.initials: C
authors.lastname: Seaman
authors.forename: Nigel
authors.initials: N
authors.lastname: Kee
authors.forename: Maria
authors.initials: M
authors.lastname: Macheda
authors.forename: Richard B
authors.initials: RB
authors.lastname: Anderson
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
authors.forename: Helen M
authors.initials: HM
authors.lastname: Cooper
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure*; D002478:Cells, Cultured; D003337:Corpus Callosum / Q000000981:diagnostic imaging* / Q000378:metabolism*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D014463:Ultrasonography; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C118148:Ryk protein, mouse