Smek1/2 is a nuclear chaperone and cofactor for cleaved Wnt receptor Ryk, regulating cortical neurogenesis

Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):E10717-E10725. doi: 10.1073/pnas.1715772114. Epub 2017 Nov 27.

Abstract

The receptor-like tyrosine kinase (Ryk), a Wnt receptor, is important for cell fate determination during corticogenesis. During neuronal differentiation, the Ryk intracellular domain (ICD) is cleaved. Cleavage of Ryk and nuclear translocation of Ryk-ICD are required for neuronal differentiation. However, the mechanism of translocation and how it regulates neuronal differentiation remain unclear. Here, we identified Smek1 and Smek2 as Ryk-ICD partners that regulate its nuclear localization and function together with Ryk-ICD in the nucleus through chromatin recruitment and gene transcription regulation. Smek1/2 double knockout mice displayed pronounced defects in the production of cortical neurons, especially interneurons, while the neural stem cell population increased. In addition, both Smek and Ryk-ICD bound to the Dlx1/2 intergenic regulator element and were involved in its transcriptional regulation. These findings demonstrate a mechanism of the Ryk signaling pathway in which Smek1/2 and Ryk-ICD work together to mediate neural cell fate during corticogenesis.

Keywords: Ryk signaling; neural stem cell; neurogenesis; noncanonical Wnt signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Coenzymes / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Molecular Chaperones / metabolism*
  • Neurogenesis / physiology*
  • Phosphoprotein Phosphatases / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism*

Substances

  • Coenzymes
  • Molecular Chaperones
  • Receptor Protein-Tyrosine Kinases
  • Ryk protein, mouse
  • Phosphoprotein Phosphatases
  • Smek1 protein, mouse
  • Smek2 protein, mouse