Prostaglandin E₂ promotes neural proliferation and differentiation and regulates Wnt target gene expression

Abstract

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.

Autism‐related behaviors in the cyclooxygenase‐2‐deficient mouse model

“…We observed sex‐specific and age‐specific differences that have never been described before in this animal model. The results presented in this study along with published clinical data as well as in vitro and in vivo molecular research strengthen the evidence that abnormal COX2/PGE2 signaling may influence brain development and contribute to ASD pathology. We determined that male and female (COX)‐2 − KI mice lacking activity from the PGE2‐producing enzyme display behaviors linked to autism, specifically in hyperactivity, anxiety, repetitive behaviors, motor strength and social interaction (Table ).…”

“…Emerging molecular evidence offers insight into possible mechanisms by which abnormal COX2/PGE2 signaling may affect brain development and lead to autism. For example, in vitro studies in our laboratory have shown that elevated levels of PGE2 can modify intracellular calcium dynamics and increase neural proliferation, migration and differentiation in neural stem cells and differentiating neurons . The expression of autism‐linked genes including Ptgs2 , Mmp9 , Ctnnb1 and Wnt3 was also altered as a result of increased PGE2 levels in these model systems .…”

Improved neural differentiation of normal and abnormal induced pluripotent stem cell lines in the presence of valproic acid

“…Apart from VPA, polyunsaturated fatty acids like docosahexaenoic acid, arachidonic acid, linoleic acid, and alpha linolenic acid have been well known to aid in the neural developmental process (Hejr et al, ; Kan, Melamed, Offen, & Green, ; Ma et al, ). Some fatty acid derivatives like Prostaglandin E2 also lead to better neurosphere development and synthesis of mature neural markers in neural stem cells (Wong et al, ).…”

Identification and Verification of Candidate Genes Regulating Neural Stem Cells Behavior Under Hypoxia

“…Furthermore, HIF-1α is also a key factor in the maintenance of the adult sub-ventricular zone and regulation of NSC biology under hypoxia [16, 18]. Besides, PTGS2 can promote neural proliferation and differentiation and influences Wnt target gene expression [51]. Using the PPI network, module analysis demonstrated that NSC behavior under hypoxia was associated with neuroactive ligand-receptor interaction, chemokine signaling pathway, calcium signaling pathway, and olfactory transduction.…”