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

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.diabetes | congenital heart defects | heterotaxia | left-right axis

Congenital eye anomalies: More mosaic than thought?

“…62 Interestingly, a recent paper reported that high glucose concentrations impede Nodal expression in cultured mouse embryos in a study focusing on laterality defects due to maternal diabetes mellitus. 63 This study implies that prenatal exposure to hyperglycemia causes HPE due to disruption of Nodal signaling when the forebrain field should be separated into two. In zebrafish, there are mutants which exhibit cyclopia: cyclops, one-eyed pinhead, bozozok, uncle freddy, and squint.…”

Left–Right Patterning: Breaking Symmetry to Asymmetric Morphogenesis

“…Extracardiac malformations including multiple spleens (polysplenia), a midline liver, and extrahepatic biliary atresia may also present in heterotaxy patients [1]. In addition to being a complex genetic condition, model organism studies suggest that abnormalities of L-R patterning can also be induced by environmental factors [3]. Another disorder, primary ciliary dyskinesia (PCD), caused by defects in motile cilia , similarly results in L-R defects including situs ambiguous or the complete reversal of organ arrangement ( situs inversus ).…”

Metabolite availability as a window to view the early embryo microenvironment in vivo

“…The low glucose concentration in oviductal fluid parallels the low‐glucose‐consumption of early embryos, and helps alleviate metabolic stress before the morula stage. Conversely, high glucose concentration or consumption is deleterious to cleavage‐stage embryos, but not morulae (Zhang et al, ), and often decreases implantation rate and poor pregnancy outcome (Chatot, Ziomek, Bavister, Lewis, & Torres, ; Conaghan et al, ; Hachisuga et al, ; Jansen, Cashman, Thompson, Pantaleon, & Kaye, ; Jansen, Esmaeilpour, Pantaleon, & Kaye, ; Wentzel and Eriksson, ; Wyman, Pinto, Sheridan, & Moley, ). Interestingly, the absence of glucose during compaction irreversibly decreased cellular proliferation and increased apoptosis (Pantaleon, Scott, & Kaye, ), probably due to increased oxidative stress (Jansen et al, ).…”