The Effect of Misoprostol on Neuronal Stem Cell Migration and Differentiation

Misoprostol is a drug commonly used for medical termination of pregnancy, and improper use has been linked to neurodevelopmental disorders such as Moebius syndrome and Autism Spectrum Disorder (ASD). It is an analog of prostaglandin type E signalling lipids, like PGE1 and PGE2, and binds the same E-Prostanoid receptors, which regulate mechanisms of neurodevelopment. Previous research from the Crawford lab found that PGE2 affected migration, differentiation, and expression of genes associated with ASD in NE-4C neuroectodermal stem cells, and neurite elongation in Neuro-2A neuroblastoma cells. The objective of this study was to determine if misoprostol alters the same cellular behaviors in NE-4C and Neuro-2A cells. Time-lapse microscopy was used to observe migration, neurosphere morphology, and neurite extension in the cell models. Misoprostol treatment decreased migration (speed and distance travelled) of NE-4C stem cells in a dose-dependent manner. Expression of stem cell marker Oct4 and neuronal marker MapT demonstrated a misoprostol induced delay in NE-4C differentiation. This was associated with changes in neurosphere morphology and expression of adhesion molecule genes, Cdh2 and NCAM. In differentiating Neuro-2A cells, chronic misoprostol exposure elongated primary neurites and branches, but decreased branch density. These results demonstrate the influence of misoprostol on cellular mechanisms of migration, differentiation, and neurite elongation, suggesting that prenatal exposure may alter these processes, resulting in abnormal neurodevelopment.