title: The ROR2 tyrosine kinase receptor regulates dendritic spine morphogenesis in hippocampal neurons.
abstract: Wnt signaling regulates synaptic development and function and contributes to the fine-tuning of the molecular and morphological differentiation of synapses. We have shown previously that Wnt5a activates non-canonical Wnt signaling to stimulate postsynaptic differentiation in excitatory hippocampal neurons promoting the clustering of the postsynaptic scaffold protein PSD-95 and the development of dendritic spines. At least three different kinds of Wnt receptors have been associated with Wnt5a signaling: seven trans-membrane Frizzled receptors and the tyrosine kinase receptors Ryk and ROR2. We report here that ROR2 is distributed in the dendrites of hippocampal neurons in close proximity to synaptic contacts and it is contained in dendritic spine protrusions. We demonstrate that ROR2 is necessary to maintain dendritic spine number and morphological distribution in cultured hippocampal neurons. ROR2 overexpression increased dendritic spine growth without affecting the density of dendritic spine protrusions in a form dependent on its extracellular Wnt binding cysteine rich domain (CRD) and kinase domain. Overexpression of dominant negative ROR2 lacking the extracellular CRD decreased spine density and the proportion of mushroom like spines, while ROR2 lacking the C-terminal and active kinase domains only affected spine morphology. Our results indicate a crucial role of the ROR2 in the formation and maturation of the postsynaptic dendritic spines in hippocampal neurons.
authors.affiliation: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile; Fundación Ciencia y Vida, Santiago 7780272, Chile; Facultad de Ciencias Naturales y Exactas, Universidad de Playa Ancha, Valparaíso, Chile.
authors.forename: Iván E
authors.initials: IE
authors.lastname: Alfaro
authors.affiliation: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile; Centro de Investigaciones Biomédicas, Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andres Bello, Santiago 8370146, Chile.
authors.forename: Lorena
authors.initials: L
authors.lastname: Varela-Nallar
authors.affiliation: Centro de Investigaciones Biomedicas, Facultad de Medicina, Universidad de los Andes, Santiago, Chile; Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
authors.forename: Manuel
authors.initials: M
authors.lastname: Varas-Godoy
authors.affiliation: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile; Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia; Centro UC Síndrome de Down, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile. Electronic address: ninestrosa@bio.puc.cl.
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism* / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D055495:Neurogenesis; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C500913:Ror2 protein, rat
keywords: Dendritic spines; Hippocampal neurons; ROR2; Synapse development; Wnt5a