Wnt-Fzd signaling sensitizes peripheral sensory neurons via distinct noncanonical pathways


  • M. Simonetti
  • N. Agarwal
  • S. Stösser
  • K.K. Bali
  • E. Karaulanov
  • R. Kamble
  • B. Pospisilova
  • M. Kurejova
  • W. Birchmeier
  • C. Niehrs
  • P. Heppenstall
  • R. Kuner


  • Neuron


  • Neuron 83 (1): 104-121


  • Wnt signaling represents a highly versatile signaling system, which plays diverse and critical roles in various aspects of neural development. Sensory neurons of the dorsal root ganglia require Wnt signaling for initial cell-fate determination as well as patterning and synapse formation. Here we report that Wnt signaling pathways persist in adult sensory neurons and play a functional role in their sensitization in a pathophysiological context. We observed that Wnt3a recruits the Wnt-calcium signaling pathway and the Wnt planar cell polarity pathway in peripheral nerves to alter pain sensitivity in a modality-specific manner and we elucidated underlying mechanisms. In contrast, biochemical, pharmacological, and genetic studies revealed lack of functional relevance for the classical canonical {beta}-catenin pathway in peripheral sensory neurons in acute modulation of nociception. Finally, this study provides proof-of-concept for a translational potential for Wnt3a-Frizzled3 signaling in alleviating disease-related pain hypersensitivity in cancer-associated pain in vivo.