title: Wnt-Fzd signaling sensitizes peripheral sensory neurons via distinct noncanonical pathways.
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.
authors.affiliation: 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.
authors.forename: Manuela
authors.initials: M
authors.lastname: Simonetti
authors.affiliation: Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Nitin
authors.initials: N
authors.lastname: Agarwal
authors.affiliation: Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stösser
authors.affiliation: 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.
authors.forename: Kiran Kumar
authors.initials: KK
authors.lastname: Bali
authors.affiliation: Institute of Molecular Biology (IMB), Mainz, Germany, Ackermannweg 4, 55128 Mainz, Germany.
authors.forename: Emil
authors.initials: E
authors.lastname: Karaulanov
authors.affiliation: Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kamble
authors.affiliation: Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Blanka
authors.initials: B
authors.lastname: Pospisilova
authors.affiliation: Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Kurejova
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Strasse 10, 13092 Berlin-Buch, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Birchmeier
authors.affiliation: 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.
authors.forename: Christof
authors.initials: C
authors.lastname: Niehrs
authors.affiliation: 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.
authors.forename: Paul
authors.initials: P
authors.lastname: Heppenstall
authors.affiliation: 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.
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051157:Frizzled Receptors / Q000502:physiology*; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology; D011984:Sensory Receptor Cells / Q000378:metabolism* / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060509:Wnt3A Protein / Q000502:physiology*
chemical_list: C105574:FZD3 protein, human; D051157:Frizzled Receptors; C555510:WNT3A protein, human; D060509:Wnt3A Protein