Wnts in action: from synapse formation to synaptic maintenance

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.

Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis

“…Numerous synaptogenic molecules, such as FGFs, Wnts, neurotrophins, Eph/ephrins, neurexins/neuroligins and leucine-rich repeat transmembrane proteins (LRRTMs), have been identified (Dai and Peng, 1995;Umemori et al, 2004;Terauchi et al, 2010;de Wit et al, 2011;Dickins and Salinas, 2013;Park and Poo, 2013;Siddiqui and Craig, 2011;Xu and Henkemeyer, 2012), but the underlying mechanisms through which they organize presynaptic differentiation are largely unknown. In this study, we demonstrated, using both in vivo and in vitro evidence, that differential use of FGFRs by FGF22 and FGF7 contributes to their presynaptic effects on excitatory and inhibitory synapses in the CA3 of the hippocampus, where the receptors are localized presynaptically in DGCs and interneurons, and that FGFR2b utilizes FRS2 and PI3K signaling to promote synaptic vesicle accumulation.…”

Downregulation of canonical Wnt signaling in hippocampus of SAMP8 mice

“…Evidence for the involvement of Wnt signaling in learning and memory processes has been reported, because it modulates synaptic function, neuronal plasticity (Dickins and Salinas, 2013;Rosso and Inestrosa, 2013), as well as adult hippocampal neurogenesis (Varela-Nallar and Inestrosa, 2013). With regard to these facts, there are considerable amounts of data that relate defects in Wnt signaling with the pathogenesis of a number of neurodegenerative and psychiatric diseases, such as AD, Parkinson's disease, schizophrenia, bipolar disorder, and autism (Berwick and Harvey, 2014;Inestrosa et al, 2012;Okerlund and Cheyette, 2011).…”

Wnt Signaling Regulates Multipolar-to-Bipolar Transition of Migrating Neurons in the Cerebral Cortex

“…Wnt ligands and components of Wnt signaling pathways are expressed during cortical development, and Wnt signaling has a well-characterized role in embryonic neurogenesis (Chenn, 2008;Rakic et al, 2009). Moreover, Wnt signaling has been implicated in dendritic development and synapse formation of cortical neurons in culture (Dickins and Salinas, 2013). Evidence indicates that Wnt proteins guide cell migration and that multiple Wnt ligands and receptors directly regulate cell polarity and motility in a variety of vertebrate and invertebrate systems (Lyuksyutova et al, 2003;Witze et al, 2008;Mentink et al, 2014).…”