Role of β-Catenin in Synaptic Vesicle Localization and Presynaptic Assembly

Abstract

Cadherins and catenins are thought to promote adhesion between pre and postsynaptic elements in the brain. Here we show a role for beta-catenin in localizing the reserved pool of vesicles at presynaptic sites. Deletion of beta-catenin in hippocampal pyramidal neurons in vivo resulted in a reduction in the number of reserved pool vesicles per synapse and an impaired response to prolonged repetitive stimulation. This corresponded to a dispersion of vesicles along the axon in cultured neurons. Interestingly, these effects are not due to beta-catenin's involvement in cadherin-mediated adhesion or wnt signaling. Instead, beta-catenin modulates vesicle localization via its PDZ binding domain to recruit PDZ proteins such as Veli to cadherin at synapses. This study defines a specific role for cadherins and catenins in synapse organization beyond their roles in mediating cell adhesion.

The tetrameric L27 domain complex as an organization platform for supramolecular assemblies

“…The mammalian orthologs of Lin-2, Lin-7 and Lin-10 are known as mammalian Lin-2 (mLin-2)/CASK, mLin-7/Velis/Mals and mLin-10/X11α/Mint1, respectively 2,6-9 . The mLin-2-mLin-7-mLin-10 tripartite complex has also been observed in the brain 2,6 , and this evolutionarily conserved protein complex has been implicated in the targeting of NMDA receptors and β-catenin assemblies to membrane subdomains in epithelia and neurons 10,11 .A bioinformatics survey reveals that L27 domain-containing proteins are invariably scaffold proteins containing multiple proteinprotein interaction domains without intrinsic enzyme activities 12 . For example, SAP97 and mLin-2/CASK, which are members of a subset of membrane-associated guanylate kinases (MAGUKs), contain one and two L27 domains, respectively, in addition to their PDZ, SH3 and guanylate kinase-like domains.…”

Catenins: playing both sides of the synapse

“…However, no spine phenotype was noted in neurons lacking β-catenin [19]. One possible explanation for this is that the highlyrelated protein plakoglobin can compensate for the absence of β-catenin in spines, as has been reported in other systems.…”

“…Proper localization and organization of synaptic vesicles along the presynaptic active zone is critical for synaptic function [1]. Loss of cadherin function [11] or loss of β-catenin [19] disrupts synaptic vesicle localization in cultured neurons, indicating that cadherin-catenin complexes function in presynaptic organization. Disruption of cadherin-catenin association with the actin cytoskeleton is not the primary cause of the defect in vesicle clustering in the absence of β-catenin.…”

“…Disruption of cadherin-catenin association with the actin cytoskeleton is not the primary cause of the defect in vesicle clustering in the absence of β-catenin. Instead, the PDZ binding domain of β-catenin is required for clustering of synaptic vesicles at presynaptic terminals [19]. Thus, the primary role of β-catenin in presynaptic organization might be to promote molecular complexes that bind and cluster synaptic vesicles at the active zone.…”

“…Finally, endogenous α-N-catenin, the neuronal form of α-catenin, is found at synapses [11], and EGFP-tagged α-Ncatenin localizes to dendritic spines and weakly to axons [17] similar to that of EGFP-tagged β-catenin. Like other cell-cell junctions, catenin localization at synapses is believed to be largely cadherin-driven [11], and evidence suggests that cadherin-catenin complexes are formed on both sides of the synapse [11,[16][17][18][19] (a model for catenin function in synapses is shown in Figure 2). However, as described earlier, there are clear structural and functional differences between the presynaptic and postsynaptic compartment.…”