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Neuron. 2014 Jul 2;83(1):104-21. doi: 10.1016/j.neuron.2014.05.037.

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

Author information

1
Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany; Molecular Medicine Partnership Unit, Otto Meyerhof Center, Im Neuenheimer Feld, 69120 Heidelberg, Germany. Electronic address: manuela.simonetti@pharma.uni-heidelberg.de.
2
Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
3
Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany; Molecular Medicine Partnership Unit, Otto Meyerhof Center, Im Neuenheimer Feld, 69120 Heidelberg, Germany.
4
Institute of Molecular Biology (IMB), Mainz, Germany, Ackermannweg 4, 55128 Mainz, Germany.
5
Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Strasse 10, 13092 Berlin-Buch, Germany.
6
Institute of Molecular Biology (IMB), Mainz, Germany, Ackermannweg 4, 55128 Mainz, Germany; Division of Molecular Embryology, DKFZ-ZMBH Alliance, Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
7
European Molecular Biology Laboratory, Adriano Buzzati-Traverso Campus, Via Ramarini 32, 00015 Monterotondo, Italy; Molecular Medicine Partnership Unit, Otto Meyerhof Center, Im Neuenheimer Feld, 69120 Heidelberg, Germany.
8
Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany; Molecular Medicine Partnership Unit, Otto Meyerhof Center, Im Neuenheimer Feld, 69120 Heidelberg, Germany. Electronic address: rohini.kuner@pharma.uni-heidelberg.de.

Abstract

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 β-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.

PMID:
24991956
DOI:
10.1016/j.neuron.2014.05.037
[Indexed for MEDLINE]
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