Maternal hyperglycaemia alters gene expression patterns in the embryo, and this may play an important role in the pathogenesis of congenital defects during diabetic pregnancy10, 16, 19, 62, 63. Alx3 deficiency in embryos exposed to high glucose concentrations in utero results in decreased expression of Ap2, Bmp4 and Pdgfrα, chosen as representative examples of genes whose deficiencies cause congenital defects that are similar to some of the craniofacial defects found in Alx3-deficient embryos. AP2 is expressed in mesenchyme cells that are important craniofacial and neural development49, 64. BMP4 and PDGFRα are signalling molecules that control different aspects of craniofacial mesenchyme differentiation51, 65. Importantly, we only detected significant changes in the expression of Ap2, Pdgfrα and Bmp4 when both Alx3 deficiency and maternal diabetes were present together. Although many other genes are likely to be affected by maternal diabetes16, 19, 62, 63, these changes represent indications that Alx3 is important for the protection of transcriptional and cell signalling programs that are critical for embryonic development from the noxious effects of hyperglycaemia. Interestingly, Gcn5 expression was not affected by Alx3 deficiency even in the presence of maternal diabetes. Since Gcn5 deficiency results in embryonic neural tube defects without affecting mesenchyme development53, this observation suggest that the impact of maternal diabetes is greater in Alx3-deficient mesenchyme cells than in other cell types in which Alx3 is not normally expressed.