Wnts acting through canonical and noncanonical signaling pathways exert opposite effects on hippocampal synapse formation

Neural Dev. 2008 Nov 5;3:32. doi: 10.1186/1749-8104-3-32.


Background: Wnt proteins comprise a large class of signaling molecules that regulate a variety of developmental processes, including synapse formation. Previous studies have shown Wnts to be involved in both the induction and prevention of synapses in a number of different organisms. However, it is not clear whether the influence of Wnts on synapses is a result of Wnts' behavior in different organisms or differences in the activity of different Wnt ligands.

Results: We used in situ hybridization to show that several Wnt ligands (Wnt3, Wnt5a, Wnt7a, and Wnt7b) and their receptors, Frizzled, are expressed in the developing hippocampus during the period of synapse formation in rodents. We used recombinant Wnt protein or Wnt conditioned media to explore the effects of Wnts on synapses in hippocampal cultures. We found that Wnt7a and Wnt7b activate canonical signaling, whereas Wnt5a activates a noncanonical pathway. The activation of the canonical pathway, either through pathway manipulations or through Wnt stimulation, increases presynaptic inputs. In contrast, exposure to Wnt5a, which activates a noncanonical signaling pathway, decreases the number of presynaptic terminals.

Conclusion: Our observations suggest that the pro- and antisynaptogenic effects of Wnt proteins are associated with the activation of the canonical and noncanonical Wnt signaling pathways.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Blotting, Western
  • Cell Culture Techniques
  • Cell Line
  • Culture Media, Conditioned / metabolism
  • Culture Media, Conditioned / pharmacology
  • Frizzled Receptors / genetics
  • Frizzled Receptors / metabolism
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Rats
  • Rats, Long-Evans
  • Signal Transduction*
  • Synapses / metabolism*
  • Transfection
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • Wnt-5a Protein
  • Wnt3 Protein


  • Culture Media, Conditioned
  • Frizzled Receptors
  • Proto-Oncogene Proteins
  • WNT3 protein, human
  • Wnt Proteins
  • Wnt-5a Protein
  • Wnt3 Protein
  • Wnt3 protein, rat
  • Wnt5a protein, rat
  • Wnt7a protein, rat