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- W4251462505 abstract "Abstract Fetal Alcohol Syndrome (FAS) is characterized by disrupted fetal brain development and postnatal cognitive impairment. The targets of alcohol are diverse and it is not clear whether there are common underlying molecular mechanisms producing these disruptions. Prior work established that acute ethanol exposure causes a transient increase in tyrosine phosphorylation of multiple proteins in cultured embryonic cortical cells. In this study we show a similar tyrosine phosphorylation transient occurs in the fetal brain after maternal dosing with ethanol. Using phospho-specific antibodies and immunohistochemistry, we mapped regions of highest tyrosine phosphorylation in the fetal cerebral cortex and found that areas of dendritic and axonal growth showed elevated tyrosine phosphorylation 10 min after maternal ethanol exposure. These were also areas of Src expression and Src Family Kinase (SFKs) activation loop phosphorylation (pY416) expression. Importantly, maternal pretreatment with the SFK inhibitor Dasatinib completely prevents both the pY416 increase and the tyrosine phosphorylation response. The phosphorylation response was observed in the perisomatic region and neurites of immature migrating and differentiating primary neurons. Importantly, the initial phosphotyrosine transient (~ 30 min) targets both Src and Dab1, two critical elements in Reelin-signaling, a pathway required for normal cortical development. This initial phosphorylation response is followed by sustained reduction in Ser3 phosphorylation of n-cofilin, a critical actin severing protein and an identified downstream effector of Reelin-signaling. This biochemical disruption is associated with sustained reduction F-actin content and disrupted Golgi-apparatus morphology in developing cortical neurons. The finding outlines a model in which the initial activation of SFKs by ethanol has the potential to disrupt multiple developmentally important signaling systems for several hours after maternal exposure." @default.
- W4251462505 created "2022-05-12" @default.
- W4251462505 creator A5033347099 @default.
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- W4251462505 date "2021-04-15" @default.
- W4251462505 modified "2023-10-17" @default.
- W4251462505 title "Maternal ethanol exposure acutely elevates Src Family Kinases activity in the fetal cortex." @default.
- W4251462505 doi "https://doi.org/10.21203/rs.3.rs-409416/v1" @default.
- W4251462505 hasPublicationYear "2021" @default.
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