In conclusion, our data reveal the existence of a novel defence mechanism to prevent congenital malformations due to oxidative stress during diabetic pregnancies. In this mechanism, Alx3 participates as a glucose-responsive gene required for the activation of Foxo1 and the subsequent stimulation of oxidative stress-scavenging genes. In humans, recessive ALX3 mutations have been shown to cause congenital craniofacial alterations34. Thus, taken together in the context of the present study, loss of function mutations in Alx3 emerge as putative determinants for increased risk of congenital craniofacial malformations associated with diabetes during pregnancy.