The increase in craniofacial but not caudal malformations observed in Alx3-deficient embryos developing in diabetic pregnancies is in good agreement with the strong expression of Alx3 in the forehead mesenchyme of wild type embryos30, 32, and indicate that in the absence of Alx3 the mesenchyme cells from this region become vulnerable to the harmfull effects of high glucose concentrations. In line with this reasoning, the most severe malformations observed in Alx3 −/− embryos from diabetic mothers could reflect, in addition, increased vulnerability of cells located in other tissues in which Alx3 is normally expressed, such as the lateral mesoderm or the serous membranes that separate internal organs30, 32. Thus, the significant increase in cranial malformations observed when Alx3 deficiency and diabetes are present together reflects the absence of a protective role for Alx3 against the teratogenic effects of glucose.