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 Ϫ/Ϫ 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 Ϫ/Ϫ 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.

Expression of Plxdc2/TEM7R in the developing nervous system of the mouse

“…In the Xoorplate, Plxdc2-geo expression is more extensive rostrocaudally than either of the Wnt genes and is not restricted to the ventricular aspect. Wnt5a expression also shows striking similarities with that of Plxdc2 in the limb (Yamaguchi et al, 1999) and in the glial wedge (see below and Keeble et al, 2006).…”

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

“…Ryk binds to Wnt through a Wnt inhibitory factor (WIF) domain, and Wnt-5a is the best-characterized ligand for Ryk. The Wnt/Ryk interaction has various roles in neurodevelopment including chemorepulsive axon guidance and neurite outgrowth (11,12). Wnt-5a/Ryk utilizes the Wnt/Ca2 1 pathway in mediating axon guidance and chemorepulsion (13).…”

The Ryk Receptor Is Expressed in Glial and Fibronectin-Expressing Cells after Spinal Cord Injury

“…[27][28][29][30][31] Much of what is known about the function of Ryk in the CNS is derived from developmental studies. During this period and among other functions, Ryk acts as a chemorepulsive axon guidance receptor during the establishment of major axon tracts, such as the corpus callosum and the corticospinal tract (CST), 32,33 and is vital for the generation of appropriate topographic maps of retinal ganglion cell axons. 34 Given the developmental role of Ryk as an essential regulator of axonal growth and the importance of this process in functional recovery following SCI, several studies have investigated the potential of this receptor to mediate axonal regeneration in experimental models of this neuropathological condition.…”