In a groundbreaking York University study, researchers have found that abnormal levels of lipid molecules in the brain can affect the interaction between two key neural pathways in early prenatal brain development, which can trigger autism. And, environmental causes such as exposure to chemicals in some cosmetics and common over-the-counter medication can affect the levels of these lipids, according to the researchers.
“We have found that the abnormal level of a lipid molecule called Prostaglandin E2 in the brain can affect the function of Wnt proteins. It is important because this can change the course of early embryonic development,” explains Professor Dorota Crawford in the Faculty of Health and a member of the York Autism Alliance Research Group.
This is the first time research shows evidence for cross-talk between PGE2 and Wnt signalling in neuronal stem cells, according to the peer reviewed study published at Cell Communication and Signaling.
Lead researcher and York U doctoral student Christine Wong adds, “Using real-time imaging microscopy, we determined that higher levels of PGE2 can change Wnt-dependent behaviour of neural stem cells by increasing cell migration or proliferation. As a result, this could affect how the brain is organized and wired. Moreover, we found that an elevated level of PGE2 can increase expression of Wnt-regulated genes — Ctnnb1, Ptgs2, Ccnd1, and Mmp9. “Interestingly, all these genes have been previously implicated in various autism studies.”
Autism is considered to be the primary disorder of brain development with symptoms ranging from mild to severe and including repetitive behaviour, deficits in social interaction, and impaired language. It is four times more prevalent in boys than in girls and the incidence continues to rise. The US Center for Disease Control and Prevention (CDC) data from 2010 estimates that 1 in 68 children now has autism.
“The statistics are alarming. It’s 30 per cent higher than the previous estimate of 1 in 88 children, up from only two years earlier. Perhaps we can no longer attribute this rise in autism incidence to better diagnostic tools or awareness of autism,” notes Crawford. “It’s even more apparent from the recent literature that the environment might have a greater impact on vulnerable genes, particularly in pregnancy. Our study provides some molecular evidence that the environment likely disrupts certain events occurring in early brain development and contributes to autism.”
According to Crawford, genes don’t undergo significant changes in evolution, so even though genetic factors are the main cause, environmental factors such as insufficient dietary supplementations of fatty acids, exposures to infections, various chemicals or drugs can change gene expression and contribute to autism.
Contact: Dorota Crawford – York University
Source: York University press release
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Original Research: Full open access research (pdf) for “Prostaglandin E2 alters Wnt-dependent migration and proliferation in neuroectodermal stem cells: implications for autism spectrum disorders” by Christine T Wong, Eizaaz Ahmad, Hongyan Li and Dorota A Crawford in Cell Communication and Signaling. Published online March 23 2014 doi:10.1186/1478-811X-12-19
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 beta-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.
Christine T Wong, Eizaaz Ahmad, Hongyan Li and Dorota A Crawford “Prostaglandin E2 alters Wnt-dependent migration and proliferation in neuroectodermal stem cells: implications for autism spectrum disorders” in Cell Communication and Signaling doi:10.1186/1478-811X-12-19.