Trends in Neurosciences
Volume 33, Issue 2, February 2010, Pages 84-92
Journal home page for Trends in Neurosciences

Review
Ryks: new partners for Wnts in the developing and regenerating nervous system

https://doi.org/10.1016/j.tins.2009.11.005Get rights and content

Conserved Ryk transmembrane proteins, tyrosine kinase-related Wnt receptors, are important during neurogenesis, axon guidance and synaptogenesis. Here, we review the increasingly complex biology of the Wnt/Ryk pathway, emphasizing the mechanisms by which Ryks transduce or sometimes block the Wnt signal. Recent studies reveal that Wnts signal through Ryk via multiple mechanisms, including nuclear translocation of their intracellular domains and pathways employing Src Family Kinases and members of the canonical Wnt pathway. We also discuss reports indicating that Wnt/Ryk axon guidance roles are evolutionarily conserved and Wnt/Ryk interactions are required for motoneuron target selection and synaptogenesis at the neuromuscular junction. Recent findings that injury-induced Wnt/Ryk pathway activation inhibits axon regeneration underscore the importance of further understanding this novel pathway.

Section snippets

Ryk: a novel Wnt receptor

Neurons extend axons over comparatively vast distances to make synaptic connections with their targets. Several evolutionarily conserved ligands, their axonal receptors and downstream signaling effectors have been implicated in growth cone guidance via attractive or repulsive mechanisms (reviewed in Refs 1, 2, 3, 4). One recently uncovered axon guidance signaling pathway involves interactions between the Wnt signaling and the Receptor Tyrosine kinase-related tyrosine kinase (Ryk)-like

Ryk signal transduction: downstream effectors and targets

Here, we first discuss studies indicating how Ryk actively transduces the Wnt signal. Second, we discuss data indicating that Ryk, acting at a distance from where it is expressed, can sequester Wnt ligands to block their function.

An early indication that Ryk can transmit an intracellular signal was the observation that treatment of cells expressing a Trk extracellular domainā€“Ryk intracellular domain fusion protein with the Trk ligand, NGF, activates the MAPK pathway [40]. No evidence, however,

Axon regeneration and injury-induced Wnt signaling

Two recent reports indicate that although the Wnt/Ryk pathway is required for axon guidance during development, inappropriate activation of this pathway after injury probably contributes to poor axon regrowth of both peripheral and central axon tracts. Wnt expression in the adult spinal cord is essentially undetectable; however, Wnt1 and WNT5a expression levels dramatically increase in rodent spinal cord gray matter and reactive astrocytes at sites of injury 54, 55 (Figure 4). Damaged cortical

Repulsive Wnt/Ryk axon guidance in the mammalian spinal cord and optical system

Three studies characterizing different aspects of Wnt/Ryk interaction in the developing mammalian brain indicate that they function to mediate repulsive axon guidance 59, 60, 61. Characterization of the Wnt and Ryk expression patterns in the developing mouse spinal cord revealed that Wnt proteins are expressed in the gray matter in a decreasing anterior to posterior gradient, whereas Ryk is expressed on CST axons [60]. Wnt1 and Wnt5a were found to repel Ryk-expressing CST axons, which could be

Concluding remarks and perspectives

In summary, there has been significant progress in determining the apparently many roles and mechanisms of Wnt/Ryk signaling during nervous system development. In addition to other outstanding issues (mentioned above and in Box 1), many questions raised by the results of these recent studies will keep Wnt researchers active for years. Among the more global questions: (i) Do the various Wnt/Ryk signal transduction mechanisms occur simultaneously in single cells or are they cell type- or

Acknowledgements

We thank Huey Hing, Patricia Salinas and Yimin Zou for comments and Yimin Zou, Edmund Hollis and Alisha Richman for kindly providing Figure 4, Figure 5.

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