Abstract
Synapses are specialized neuronal connections essential for neuronal function. Defects in synaptic assembly or maintenance usually lead to various neurological disorders. Synaptic assembly is regulated by secreted molecules such as Wnts. Wnts are a large family of conserved glycosylated signaling molecules involved in many aspects of neural development and maintenance. However, the molecular mechanisms by which Wnts regulate synaptic assembly remain elusive due to the large number of ligands/receptors, the diversity of signaling cascades and the complexity of the nervous system. In this study, through genetic manipulation, we uncover that C. elegans Wnt-2 (CWN-2) is required for synaptic development. The CWN-2 signal is required during both embryonic and postembryonic development, in the nervous system and intestine, for promoting synaptic assembly. Furthermore, we provide genetic evidence for CWN-2 promoting synaptogenesis through the Frizzled receptor (FZD) CFZ-2, the Dishevelled (DVL) DSH-2, the β-catenin SYS-1 and the only T-cell specific transcription factor POP-1/TCF. Importantly, it is the first time to report the requirement of a TCF for presynaptic assembly. These findings expand our understanding of the synaptogenic mechanisms and may provide therapeutic insights into Wnt-related neurological disorders.
Highlights
Normal neural function requires precise synaptic connections, and defects in the connection often result in neurological disorders (Caracci et al, 2016; Remedio et al, 2016; Song et al, 2016, 2017; Roeper, 2017; Zhai et al, 2017; Moretto et al, 2018)
To test whether Wnts are required for synaptic clustering, we examined the Amphid interneuron (AIY) synaptic vesicle marker Green fluorescent protein (GFP)::RAB-3 clustering phenotype in all four viable Wnt loss of function mutants: cwn-1(ok546), cwn-2(ok895), egl-20(n585), lin44(n1792; their genetic lesions are shown in Figure 1C, Supplementary Figures S2A–C), and in the essential Wnt mom-2 knockdown animals
The requirement of cwn2 for GFP::RAB-3 clustering is further confirmed by the fact that the AIY synaptic defect in cwn-2(ok895) mutants can be rescued by expressing the wild type cwn-2 transgene in cwn-2(ok895) mutants (P < 0.0001 for Zone 2 fragmentation, P < 0.05 for GFP intensity, Figures 1F–H)
Summary
Normal neural function requires precise synaptic connections, and defects in the connection often result in neurological disorders (Caracci et al, 2016; Remedio et al, 2016; Song et al, 2016, 2017; Roeper, 2017; Zhai et al, 2017; Moretto et al, 2018). In Drosophila, Wnts act through the Frizzled (FZD) nuclear import signaling pathway (Mathew et al, 2005)
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