Hyperglycemia impairs left–right axis formation and thereby disturbs heart morphogenesis in mouse embryos

Congenital heart defects with heterotaxia are associated with pregestational diabetes mellitus. To provide insight into the mechanisms underlying such diabetes-related heart defects, we examined the effects of high-glucose concentrations on formation of the left–right axis in mouse embryos. Expressi...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2015-09, Vol.112 (38), p.E5300-E5307
Main Authors: Hachisuga, Masahiro, Oki, Shinya, Kitajima, Keiko, Ikuta, Satomi, Sumi, Tomoyuki, Kato, Kiyoko, Wake, Norio, Meno, Chikara
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Blood Glucose - chemistry
Body Patterning - genetics
Disease Models, Animal
Embryonic Stem Cells - cytology
Embryos
Female
Gene expression
Gene Expression Regulation, Developmental
Glucose - chemistry
Glucose - metabolism
Heart
Heart - physiology
Heart Defects, Congenital - physiopathology
HEK293 Cells
Humans
Hyperglycemia
Hyperglycemia - physiopathology
Mesoderm - physiology
Mice
Microscopy, Electron, Scanning
Morphogenesis
Morphogenesis - genetics
Phosphorylation
PNAS Plus
Receptors, Notch - metabolism
Rodents
Signal Transduction
Time Factors
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Summary:Congenital heart defects with heterotaxia are associated with pregestational diabetes mellitus. To provide insight into the mechanisms underlying such diabetes-related heart defects, we examined the effects of high-glucose concentrations on formation of the left–right axis in mouse embryos. Expression ofPitx2, which plays a key role in left–right asymmetric morphogenesis and cardiac development, was lost in the left lateral plate mesoderm of embryos of diabetic dams. Embryos exposed to high-glucose concentrations in culture also failed to expressNodalandPitx2in the left lateral plate mesoderm. The distribution of phosphorylated Smad2 revealed that Nodal activity in the node was attenuated, accounting for the failure of left–right axis formation. Consistent with this notion, Notch signal-dependent expression of Nodal-related genes in the node was also down-regulated in association with a reduced level of Notch signaling, suggesting that high-glucose concentrations impede Notch signaling and thereby hinder establishment of the left–right axis required for heart morphogenesis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1504529112