Cleavage of the Wnt receptor Ryk regulates neuronal differentiation during cortical neurogenesis

Dev Cell. 2008 Nov;15(5):773-80. doi: 10.1016/j.devcel.2008.10.004.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • COS Cells
  • Cell Differentiation*
  • Cell Nucleus / metabolism
  • Chlorocebus aethiops
  • Embryo, Mammalian / metabolism
  • Mice
  • Neurons / cytology*
  • Protein Structure, Tertiary
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction
  • Stem Cells / cytology*
  • Wnt Proteins / metabolism
  • Wnt3 Protein


  • Wnt Proteins
  • Wnt3 Protein
  • Wnt3 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Ryk protein, mouse
  • Amyloid Precursor Protein Secretases