Prostaglandin E2 alters Wnt-dependent migration and proliferation in neuroectodermal stem cells: implications for autism spectrum disorders.

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.
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