title: Prostaglandin E2 alters Wnt-dependent migration and proliferation in neuroectodermal stem cells: implications for autism spectrum disorders.
abstract: Prostaglandin E2 (PGE2) is a natural lipid-derived molecule that is involved in important physiological functions. Abnormal PGE2 signalling has been associated with pathologies of the nervous system. Previous studies provide evidence for the interaction of PGE2 and canonical Wnt signalling pathways in non-neuronal cells. Since the Wnt pathway is crucial in the development and organization of the brain, the main goal of this study is to determine whether collaboration between these pathways exists in neuronal cell types. We report that PGE2 interacts with canonical Wnt signalling through PKA and PI-3K in neuroectodermal (NE-4C) stem cells. We used time-lapse microscopy to determine that PGE2 increases the final distance from origin, path length travelled, and the average speed of migration in Wnt-activated cells. Furthermore, PGE2 alters distinct cellular phenotypes that are characteristic of Wnt-induced NE-4C cells, which corresponds to the modified splitting behaviour of the cells. We also found that in Wnt-induced cells the level of β-catenin protein was increased and the expression levels of Wnt-target genes (Ctnnb1, Ptgs2, Ccnd1, Mmp9) was significantly upregulated in response to PGE2 treatment. This confirms that PGE2 activated the canonical Wnt signalling pathway. Furthermore, the upregulated genes have been previously associated with ASD. Our findings show, for the first time, evidence for cross-talk between PGE2 and Wnt signalling in neuronal cells, where PKA and PI-3K might act as mediators between the two pathways. Given the importance of PGE2 and Wnt signalling in prenatal development of the nervous system, our study provides insight into how interaction between these two pathways may influence neurodevelopment.
authors.forename: Christine T
authors.initials: CT
authors.lastname: Wong
authors.forename: Eizaaz
authors.initials: E
authors.lastname: Ahmad
authors.forename: Hongyan
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Kinesiology and Health Science, York University, 4700 Keele Street, Toronto, Ontario M3J 1P3, Canada. dakc@yorku.ca.
authors.forename: Dorota A
authors.initials: DA
authors.lastname: Crawford
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002659:Child Development Disorders, Pervasive / Q000209:etiology / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D054258:Neural Plate / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; C530105:Ccnd1 protein, mouse; D051176:beta Catenin; D019938:Cyclin D1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D015232:Dinoprostone