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

Elizabeth K Davis,Anirvan Ghosh,Yimin Zou

doi:10.1186/1749-8104-3-32

Elizabeth K Davis, Anirvan Ghosh + Show 1 more

Open Access

https://doi.org/10.1186/1749-8104-3-32

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Journal: Neural Development	Publication Date: Nov 5, 2008
Citations: 171	License type: cc-by

Affiliation: University of California, San Diego

Abstract

BackgroundWnt 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.ResultsWe 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.ConclusionOur observations suggest that the pro- and antisynaptogenic effects of Wnt proteins are associated with the activation of the canonical and noncanonical Wnt signaling pathways.

Highlights

Wnt proteins comprise a large class of signaling molecules that regulate a variety of developmental processes, including synapse formation
Wnts and Frizzled proteins (Fzd) are expressed in the hippocampus during synapse formation To determine which Wnts might be involved in synapse formation, we performed an in situ hybridization screen to identify Wnts that are expressed in the hippocampus during synaptogenesis
We found that Fzd3 colocalized with some Vesicular glutamate transporter 1 (VGLUT1) puncta (Figure 3C, arrows), but other VGLUT1 puncta did not colocalize with Fzd3 (Figure 3C, asterisks)

Summary

Introduction

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. The canonical pathway begins with activation of Fzd and a low-density lipoprotein receptor-related protein (LRP)5/6 coreceptor, resulting in the phosphorylation of Disheveled (Dvl). Dvl disrupts a complex of proteins that consists of Axin, APC, and glycogen synthase kinase (GSK)3β. This complex normally degrades β-catenin through phosphorylation, so when Wnts bind, β-catenin levels are stabilized. New Wnt signaling pathways that act through Fzd or various other receptors are emerging [4]

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