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

Masahiro Hachisuga,Shinya Oki,Keiko Kitajima,Satomi Ikuta,Tomoyuki Sumi,Kiyoko Kato,Norio Wake,Chikara Meno

doi:10.1073/pnas.1504529112

Abstract

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.

Highlights

Congenital heart defects with heterotaxia are associated with pregestational diabetes mellitus
Nodal produced in the crown cells forms a heterodimer with a TGF-β family member, growth differentiation factor 1 (GDF1), which increases its activity, and it is thought to diffuse to the lateral plate mesoderm (LPM) [30, 31]
We found that high-glucose levels prevent establishment of the L–R axis required for heart morphogenesis and the L–R asymmetry of visceral organs

Summary

Introduction

Congenital heart defects with heterotaxia are associated with pregestational diabetes mellitus. We have examined left–right (L–R) axis formation in embryos of diabetic female mice as well as in mouse embryos exposed to high-glucose concentrations in culture. Nodal signaling in the left LPM and heart primordium induces the expression of the homeobox gene Pitx2 [39, 40], as a result of which visceral organs acquire their L–R asymmetric morphology.

Results

Conclusion