Prostaglandin E2 promotes neural proliferation and differentiation and regulates Wnt target gene expression.
Prostaglandin E2 (PGE2 ) 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 PGE2 levels in the developing brain and have been associated with autism disorders. This study seeks to determine whether changes in PGE2 level can alter the behavior of undifferentiated and differentiating neuroectodermal (NE-4C) stem cells and whether PGE2 signaling impinges on the Wnt/β-catenin pathways. We show that PGE2 increases proliferation of undifferentiated NE-4C stem cells. PGE2 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, PGE2 alters the expression of downstream Wnt-regulated genes previously associated with neurodevelopmental disorders. In undifferentiated stem cells, PGE2 downregulates Ptgs2 expression and upregulates Mmp9 and Ccnd1 expression. In differentiating neuronal cells, PGE2 causes upregulation of Wnt3, Tcf4, and Ccnd1. The convergence of the PGE2 and the Wnt pathways is also apparent through increased expression of active β-catenin, a key signaling component of the Wnt/β-catenin pathways. This study provides novel evidence that PGE2 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. © 2016 Wiley Periodicals, Inc.
School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.|Neuroscience Graduate Diploma Program, York University, Toronto, Ontario, Canada.
Christine T
CT
Wong
Department of Biology, York University, Toronto, Ontario, Canada.
Netta
N
Ussyshkin
Neuroscience Graduate Diploma Program, York University, Toronto, Ontario, Canada.|Department of Biology, York University, Toronto, Ontario, Canada.
Eizaaz
E
Ahmad
Neuroscience Graduate Diploma Program, York University, Toronto, Ontario, Canada.|Department of Biology, York University, Toronto, Ontario, Canada.
Ravneet
R
Rai-Bhogal
School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
Hongyan
H
Li
School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.|Neuroscience Graduate Diploma Program, York University, Toronto, Ontario, Canada.|Department of Biology, York University, Toronto, Ontario, Canada.
Dorota A
DA
Crawford
D000818:Animals; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D015232:Dinoprostone / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics
D015820:Cadherins; C530105:Ccnd1 protein, mouse; D019938:Cyclin D1; D015232:Dinoprostone
Wnt; autism; cell differentiation; cell proliferation; lipid signaling; neural stem cell; neurodevelopment; prostaglandin