Cleavage of the Wnt Receptor Ryk Regulates Neuronal Differentiation during Cortical Neurogenesis

Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
Developmental Cell (Impact Factor: 10.37). 12/2008; 15(5):773-80. DOI: 10.1016/j.devcel.2008.10.004
Source: PubMed

ABSTRACT Ryk is a transmembrane receptor tyrosine kinase (RTK). It functions as a receptor of Wnt proteins required for cell-fate determination, axon guidance, and neurite outgrowth in different organisms; however, the molecular mechanism of Ryk signaling is unknown. Here, we show that Ryk is cleaved, permitting the intracellular C-terminal fragment of Ryk to translocate to the nucleus in response to Wnt3 stimulation. We also show that the cleaved intracellular domain of Ryk is required for Wnt3-induced neuronal differentiation in vitro and in vivo. These results demonstrate an unexpected mechanism of signal transduction for Ryk as a Wnt receptor, in which the intracellular domain itself functions as the transducing molecule to bring extracellular signals from the cell surface into the nucleus, to regulate neural progenitor cell differentiation.

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    • "Subsequently, a C-terminal cleavage product, DFz2C, is imported into the nucleus (Mathew et al., 2005) via canonical nuclear import machinery (Mosca and Schwarz, 2010) where it localizes to discrete foci (Ataman et al., 2008; Mathew et al., 2005). A similar transduction pathway has been reported for the Wnt receptor Ryk during mammalian cortical neuron development (Lyu et al., 2008). However, the nuclear function of these DFz2C/Ryk C-terminal fragments remains unexplored. "
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    • "In this pathway, the Wnt receptor Frizzled-2 (DFz2) is endocytosed by the postsynaptic muscle cell and a C terminal cleavage fragment is then translocated to the nucleus (Mathew et al., 2005). An analogous pathway has been described during the differentiation of cortical neurons by the atypical Wnt receptor Ryk/Derailed (Lyu et al., 2008). Alterations in the Frizzled Nuclear import pathway interfere with the proliferation of synaptic boutons during neuromuscular junction expansion, the formation of active zones, and the recruitment of postsynaptic proteins. "
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