Signaling across the synapse: a role for Wnt and Dishevelled in presynaptic assembly and neurotransmitter release

Azlina Ahmad-Annuar,Stephen Brickley,Judit Herreros,Silvana B Rosso,Lorenza Ciani,Naila Ben Fredj,Iordanis Simeonidis,Anita Hall,Patricia C Salinas

doi:10.1083/jcb.200511054

Azlina Ahmad-Annuar, Stephen Brickley + Show 7 more

Open Access

https://doi.org/10.1083/jcb.200511054

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Abstract

Proper dialogue between presynaptic neurons and their targets is essential for correct synaptic assembly and function. At central synapses, Wnt proteins function as retrograde signals to regulate axon remodeling and the accumulation of presynaptic proteins. Loss of Wnt7a function leads to defects in the localization of presynaptic markers and in the morphology of the presynaptic axons. We show that loss of function of Dishevelled-1 (Dvl1) mimics and enhances the Wnt7a phenotype in the cerebellum. Although active zones appear normal, electrophysiological recordings in cerebellar slices from Wnt7a/Dvl1 double mutant mice reveal a defect in neurotransmitter release at mossy fiber–granule cell synapses. Deficiency in Dvl1 decreases, whereas exposure to Wnt increases, synaptic vesicle recycling in mossy fibers. Dvl increases the number of Bassoon clusters, and like other components of the Wnt pathway, it localizes to synaptic sites. These findings demonstrate that Wnts signal across the synapse on Dvl-expressing presynaptic terminals to regulate synaptic assembly and suggest a potential novel function for Wnts in neurotransmitter release.

Highlights

During the formation of synaptic connections, axons remodel and begin to assemble the machinery required for neurotransmitter release upon arrival to their synaptic targets
To examine whether Dvl localizes to stable synaptic sites, Dvl1-HA and PSD95-GFP were expressed in 14 d in vitro (DIV) cultures
We show that Dvl1 is required for proper Wnt signaling during synapse formation

Summary

Introduction

During the formation of synaptic connections, axons remodel and begin to assemble the machinery required for neurotransmitter release upon arrival to their synaptic targets. Synapses are formed through a sequence of events in which secreted factors stimulate neuronal maturation, priming neurons for synapse formation followed by the focal action of membrane proteins that stimulate synaptic assembly This model has not been fully tested and, Wnt signaling plays a key role in diverse aspects of neuronal connectivity by regulating axon guidance, dendritic development, axon remodeling and synapse formation (Ciani and Salinas, 2005). The extensive interdigitation of several GC dendrites into a single MF axon leads to a significant increase in the area of contact and is thought to contribute to some of the unusual functional properties observed at the MF-GC synapse (DiGregorio et al, 2002; Xu-Friedman and Regehr, 2003) These morphological changes are concurrent with the accumulation of presynaptic proteins and the formation of active zones. Wnt7a functions as a retrograde GC signal that acts on MF axons to regulate presynaptic differentiation

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