Abstract
A proper balance between synapse assembly and disassembly is crucial for the formation of functional neuronal circuits and synaptic plasticity in the adult brain. During development, synaptogenesis generates a vast excess of synapses, which are subsequently eliminated. Importantly, aberrant synaptic disassembly during development underpins many neurological disorders. Wnt secreted proteins are robust synaptogenic factors that regulate synapse assembly and function in the developing and mature brain. Recent studies show that Wnt blockade with the antagonist Dickkopf-1 (Dkk1) induces the rapid disassembly of synapses in mature neurons. Importantly, Dkk1 mediates synaptic loss induced by Amyloid-ß, a key pathogenic molecule in Alzheimer’s disease (AD). These findings provide new insights into the potential contribution of dysfunctional Wnt signaling to synaptic loss observed in neurodegenerative diseases. In this review, we discuss the role of Wnt signaling in vertebrate synaptic assembly, function and maintenance, and consider how dysfunction of Wnt signaling could contribute to synaptic disassembly in neurodegenerative diseases such as AD.
Highlights
During early development, Wnts regulate critical cellular processes such as cell proliferation and cell fate, neuronal polarity and migration
The array of diverse cellular processes regulated by Wnt signaling is achieved through multiple Wnt ligands interacting with numerous receptors and co-receptors that trigger distinct signaling cascades that induce local changes and/or global changes through the modulation of target gene expression (Mikels and Nusse, 2006; Kikuchi et al, 2007; van Amerongen and Nusse, 2009)
Blockade of transcription by RNA polymerase inhibition does not affect Wnt mediated presynaptic assembly (EM Dickins and PC Salinas, unpublished results) neither axonal remodeling, a process that precedes presynaptic assembly (Purro et al, 2008). These results suggest that Wnt might signal locally to regulate Dvl1 and Gsk3β to promote presynaptic assembly
Summary
A proper balance between synapse assembly and disassembly is crucial for the formation of functional neuronal circuits and synaptic plasticity in the adult brain. Wnt secreted proteins are robust synaptogenic factors that regulate synapse assembly and function in the developing and mature brain. Dkk mediates synaptic loss induced by Amyloid-ß, a key pathogenic molecule in Alzheimer’s disease (AD). These findings provide new insights into the potential contribution of dysfunctional Wnt signaling to synaptic loss observed in neurodegenerative diseases. We discuss the role of Wnt signaling in vertebrate synaptic assembly, function and maintenance, and consider how dysfunction of Wnt signaling could contribute to synaptic disassembly in neurodegenerative diseases such as AD
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