Prostaglandin E2 alters Wnt-dependent migration and proliferation in neuroectodermal stem cells: implications for autism spectrum disorders

Abstract

Prostaglandin E2 (PGE ₂) is a natural lipid-derived molecule that is involved in important physiological functions. Abnormal PGE ₂ signalling has been associated with pathologies of the nervous system. Previous studies provide evidence for the interaction of PGE ₂ 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 PGE ₂ interacts with canonical Wnt signalling through PKA and PI-3K in neuroectodermal (NE-4C) stem cells. We used time-lapse microscopy to determine that PGE ₂ increases the final distance from origin, path length travelled, and the average speed of migration in Wnt-activated cells. Furthermore, PGE ₂ 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 PGE ₂ treatment. This confirms that PGE ₂ 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 PGE ₂ and Wnt signalling in neuronal cells, where PKA and PI-3K might act as mediators between the two pathways. Given the importance of PGE ₂ and Wnt signalling in prenatal development of the nervous system, our study provides insight into how interaction between these two pathways may influence neurodevelopment.