Wnt-5a/Frizzled9 Receptor Signaling through the Gαo-Gβγ Complex Regulates Dendritic Spine Formation.

RAMIREZ; RAMOS-FERNANDEZ; HENRIQUEZ; ALFREDO LORENZO; DD NIBALDO INESTROSA

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Lugar: Bethesda, Maryland; Año: 2016

0021-9258

Wntligands play crucial roles in the development and regulation of synapsestructure and function. Specifically, Wnt-5a acts as a secreted growth factorthat regulates dendritic spine formation in rodent hippocampal neurons,resulting in postsynaptic development that promotes the clustering of thePSD-95 (postsynaptic density protein 95). Here, we focused on the early eventsoccurring after the interaction between Wnt-5a and its Frizzled receptor at theneuronal cell surface. Additionally, we studied the role of heterotrimeric Gproteins in Wnt-5a-dependent synaptic development. We report that FZD9(Frizzled9), a Wnt receptor related to Williams syndrome, is localized in thepostsynaptic region, where it interacts with Wnt-5a. Functionally, FZD9 isrequired for the Wnt-5a-mediated increase in dendritic spine density. FZD9forms a precoupled complex with Gαo under basal conditions that dissociates afterWnt-5a stimulation. Accordingly, we found that G protein inhibition abrogatesthe Wnt-5a-dependent pathway in hippocampal neurons. In particular, theactivation of Gαo appears to be a key factor controlling theWnt-5a-induced dendritic spine density. In addition, we found that Gβγ isrequired for the Wnt-5a-mediated increase in cytosolic calcium levels and spinogenesis.Our findings reveal that FZD9 and heterotrimeric G proteins regulate Wnt-5asignaling and dendritic spines in cultured hippocampal neurons.