Impact of protein O-GlcNAcylation on neural tube malformation in diabetic embryopathy
PublisherNature Publishing Group
MetadataShow full item record
AbstractDiabetes mellitus in early pregnancy can cause neural tube defects (NTDs) in embryos by perturbing protein activity, causing cellular stress, and increasing programmed cell death (apoptosis) in the tissues required for neurulation. Hyperglycemia augments a branch pathway in glycolysis, the hexosamine biosynthetic pathway (HBP), to increase uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc). GlcNAc can be added to proteins by O-GlcNAc transferase (OGT) to regulate protein activity. In the embryos of diabetic mice, OGT is highly activated in association with increases in global protein O-GlcNAcylation. In neural stem cells in vitro, high glucose elevates O-GlcNAcylation and reactive oxygen species, but the elevations can be suppressed by an OGT inhibitor. Inhibition of OGT in diabetic pregnant mice in vivo decreases NTD rate in the embryos. This effect is associated with reduction in global O-GlcNAcylation, alleviation of intracellular stress, and decreases in apoptosis in the embryos. These suggest that OGT plays an important role in diabetic embryopathy via increasing protein O-GlcNAcylation, and that inhibiting OGT could be a candidate approach to prevent birth defects in diabetic pregnancies. Copyright 2017 The Author(s).
SponsorsThe authors thank Hua Li for technical assistance, Dr. Min Zhan for statistical analyses, and Dr. Julie Rosen for critical reading and editing. The work was supported by the National Institutes of Health under Award Numbers HD076245 and HD075995.
Neural Tube Defects
Protein Processing, Post-Translational
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85029230465&doi=10.1038%2fs41598-017-11655-6&partnerID=40&md5=e23432109f6f8357eeebfb85043898e5; http://hdl.handle.net/10713/11132
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