title: Wnt-5a/Frizzled9 Receptor Signaling through the Gαo-Gβγ Complex Regulates Dendritic Spine Formation.
abstract: Wnt ligands play crucial roles in the development and regulation of synapse structure and function. Specifically, Wnt-5a acts as a secreted growth factor that regulates dendritic spine formation in rodent hippocampal neurons, resulting in postsynaptic development that promotes the clustering of the PSD-95 (postsynaptic density protein 95). Here, we focused on the early events occurring after the interaction between Wnt-5a and its Frizzled receptor at the neuronal cell surface. Additionally, we studied the role of heterotrimeric G proteins in Wnt-5a-dependent synaptic development. We report that FZD9 (Frizzled9), a Wnt receptor related to Williams syndrome, is localized in the postsynaptic region, where it interacts with Wnt-5a. Functionally, FZD9 is required for the Wnt-5a-mediated increase in dendritic spine density. FZD9 forms a precoupled complex with Gαo under basal conditions that dissociates after Wnt-5a stimulation. Accordingly, we found that G protein inhibition abrogates the Wnt-5a-dependent pathway in hippocampal neurons. In particular, the activation of Gαo appears to be a key factor controlling the Wnt-5a-induced dendritic spine density. In addition, we found that Gβγ is required for the Wnt-5a-mediated increase in cytosolic calcium levels and spinogenesis. Our findings reveal that FZD9 and heterotrimeric G proteins regulate Wnt-5a signaling and dendritic spines in cultured hippocampal neurons.
authors.affiliation: From the Centro de Envejecimiento y Regeneración, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8331150 Santiago, Chile.
authors.forename: Valerie T
authors.initials: VT
authors.lastname: Ramírez
authors.affiliation: From the Centro de Envejecimiento y Regeneración, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8331150 Santiago, Chile.
authors.forename: Eva
authors.initials: E
authors.lastname: Ramos-Fernández
authors.affiliation: the Laboratorio de Neurobiología del Desarrollo, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Núcleo Milenio de Biología Regenerativa, Centro de Microscopía Avanzada, Universidad de Concepción, 4089100 Concepción, Chile.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Henríquez
authors.affiliation: the Laboratorio de Neuropatología Experimental, Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC-CONICET, Universidad Nacional de Córdoba, 5016 Córdoba, Argentina.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Lorenzo
authors.affiliation: From the Centro de Envejecimiento y Regeneración, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8331150 Santiago, Chile, the Center for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, 2031 New South Wales, Australia, and the Centro de Excelencia en Biomedicina de Magallanes, Universidad de Magallanes, 6200000 Punta Arenas, Chile ninestrosa@bio.puc.cl.
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D049229:Dendritic Spines / Q000235:genetics / Q000378:metabolism*; D051157:Frizzled Receptors; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism*; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D017981:Receptors, Neurotransmitter / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071818:Wnt-5a Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051157:Frizzled Receptors; C403212:Fzd9 protein, mouse; C498590:Fzd9 protein, rat; D044385:GTP-Binding Protein alpha Subunits; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D017981:Receptors, Neurotransmitter; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; C491837:Wnt5a protein, rat
keywords: Frizzled receptor; G protein-coupled receptor (GPCR); Wnt signaling; dendritic spine; heterotrimeric G protein; hippocampal neuron; synaptic plasticity