Daam2-PIP5K is a regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS

Neuron. 2015 Mar 18;85(6):1227-43. doi: 10.1016/j.neuron.2015.02.024. Epub 2015 Mar 5.


Wnt signaling plays an essential role in developmental and regenerative myelination of the CNS; however, contributions of proximal regulators of the Wnt receptor complex to these processes remain undefined. To identify components of the Wnt pathway that regulate these processes, we applied a multifaceted discovery platform and found that Daam2-PIP5K comprise a novel pathway regulating Wnt signaling and myelination. Using dorsal patterning of the chick spinal cord we found that Daam2 promotes Wnt signaling and receptor complex formation through PIP5K-PIP2. Analysis of Daam2 function in oligodendrocytes (OLs) revealed that it suppresses OL differentiation during development, after white matter injury (WMI), and is expressed in human white matter lesions. These findings suggest a pharmacological strategy to inhibit Daam2-PIP5K function, application of which stimulates remyelination after WMI. Put together, our studies integrate information from multiple systems to identify a novel regulatory pathway for Wnt signaling and potential therapeutic target for WMI.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Mice
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Myelin Sheath / metabolism
  • Oligodendroglia / cytology*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Regeneration / physiology
  • Signal Transduction / physiology
  • Spinal Cord / metabolism*
  • Spinal Cord / pathology
  • White Matter / injuries
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway*
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism*


  • Daam2 protein, mouse
  • Microfilament Proteins
  • Wnt Proteins
  • Phosphotransferases (Alcohol Group Acceptor)
  • rho GTP-Binding Proteins