Synapse formation is a critical step in the assembly of neuronal circuits. Both secreted and membrane-associated proteins contribute to the assembly and maturation of synapses. In addition, neuronal activity regulates the formation of neuronal circuits through the stimulation of growth factor secretion and the localization of receptors such as NMDA and AMPA receptors (NMDAR and AMPAR, respectively). Little is known, however, about the role of activity in the localization and function of receptors for synaptogenic molecules. Wnts are secreted proteins that play a role in synapse formation by regulating pre- and postsynaptic assembly at central and peripheral synapses. Wnts can signal through different receptors including Frizzleds (Fzs), the LRP5/6 coreceptors, Ror and Ryk. Fz receptors have been shown to mediate Wnt function during synapse formation. At the cell surface, Fz receptors are located at synaptic and extrasynaptic sites. Importantly, synaptic localization of Fzs is regulated by neuronal activity in a Wnt-dependent manner. In this review, we discuss the function of Wnt-Fz signaling in the assembly of central and peripheral synapses and the evidence supporting a role for Wnt ligands and their Fz receptors in activity-mediated synapse formation.
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