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. Expression of Pitx2, 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 express Nodal and Pitx2 in 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.
Department of Developmental Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Masahiro
M
Hachisuga
Department of Developmental Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
Shinya
S
Oki
Department of Developmental Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
Keiko
K
Kitajima
Department of Developmental Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
Satomi
S
Ikuta
Department of Developmental Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
Tomoyuki
T
Sumi
Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Kiyoko
K
Kato
Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Norio
N
Wake
Department of Developmental Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; meno@dev.med.kyushu-u.ac.jp.
Chikara
C
Meno
D000818:Animals; D001786:Blood Glucose / Q000737:chemistry; D019521:Body Patterning / Q000235:genetics*; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005947:Glucose / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006321:Heart / Q000502:physiology*; D006330:Heart Defects, Congenital / Q000503:physiopathology; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D008648:Mesoderm / Q000502:physiology; D051379:Mice; D008855:Microscopy, Electron, Scanning; D009024:Morphogenesis / Q000235:genetics; D010766:Phosphorylation; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D001786:Blood Glucose; D051880:Receptors, Notch; D005947:Glucose
congenital heart defects; diabetes; heterotaxia; left–right axis