Prostaglandin E2 Promotes Neural Proliferation and Differentiation and Regulates Wnt Target Gene Expression

Prostaglandin E-2 (PGE(2)) is an endogenous lipid molecule that regulates important physiological functions, including calcium signaling, neuronal plasticity, and immune responses. Exogenous factors such as diet, exposure to immunological agents, toxic chemicals, and drugs can influence PGE(2) levels in the developing brain and have been associated with autism disorders. This study seeks to determine whether changes in PGE(2) level can alter the behavior of undifferentiated and differentiating neuroectodermal (NE-4C) stem cells and whether PGE(2) signaling impinges on the Wnt/beta-catenin pathways. We show that PGE(2) increases proliferation of undifferentiated NE-4C stem cells. PGE(2) also promotes the progression of NE-4C stem cell differentiation into neuronal-lineage cells, which is apparent by accelerated appearance of neuronal clusters (neurospheres) and earlier expression of the neuronal marker microtubule-associated protein tau. Furthermore, PGE(2) alters the expression of downstream Wnt-regulated genes previously associated with neurodevelopmental disorders. In undifferentiated stem cells, PGE(2) downregulates Ptgs2 expression and upregulates Mmp9 and Ccnd1 expression. In differentiating neuronal cells, PGE(2) causes upregulation of Wnt3, Tcf4, and Ccnd1. The convergence of the PGE(2) and the Wnt pathways is also apparent through increased expression of active beta-catenin, a key signaling component of the Wnt/beta-catenin pathways. This study provides novel evidence that PGE(2) influences progression of neuronal development and influences Wnt target gene expression. We discuss how these findings could have potential implications for neurodevelopmental disorders such as autism. (C) 2016 Wiley Periodicals, Inc.