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.

Multiple sevoflurane exposures during pregnancy inhibit neuronal migration by upregulating prostaglandin D2 synthase

“…Wong et al reported that in neuronal cells, through PKA and PI‐3 K, prostaglandin E2 can activate the canonical Wnt signaling pathway and alter the average speed of migration in Wnt‐activated cells. Thus, Ptgds may also exert its effect on neuronal migration through the Wnt signaling pathway (Wong et al, 2014). Although this is an animal study and focuses solely on one aspect of brain development, our findings suggest a novel non‐enzymatic function of Ptgds protein in brain neurotoxicity.…”

Prenatal exposure to common environmental factors affects brain lipids and increases risk of developing autism spectrum disorders

“…PGE 2 is important in various brain functions, including the masculinization of the brain and behavior (Amateau & McCarthy, ; Lenz et al ., ), dendritic spine formation (Amateau & McCarthy, ), synaptic plasticity (Koch et al ., ), calcium regulation in growth cones (Tamiji & Crawford ), and the survival, proliferation, migration and differentiation of neural stem cells (Jiang et al ., ). Moreover, it is capable of modifying the signaling of crucial developmental pathways, including the Wnt signaling pathway (Buchanan & DuBois, ; Evans, ; Goessling et al ., ; Wong et al ., ).…”

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

“…In vitro cell migration assays using mouse NSCs indicate that Wnt/β-catenin signaling also promotes cell migration via cross talk with prostaglandin E2 (PGE2) signaling. This pathway leads to transcriptional upregulation of Ctnnb1 , Ptgs2 , Ccnd1 , Mmp9 [137] - all of which, likely not coincidentally, have been linked to the etiopathology of ASD and Scz [138,139,140,141,142,143,144,145]. …”