The observation that maternal diabetes induced the expression of Hif1α in wild type but not in Alx3-deficient embryos is in agreement with studies showing an increase in Hif1α mRNA and protein levels in diabetes-exposed mouse embryos16, 41. Although the regulation of many of the cellular functions of HIF1α has been described to operate at the protein level, increasing evidence indicates that transcriptional control of its expression plays an important role58. In this regard, Hif1α expression increases in response to glucose via regulation at the promoter level59. During diabetic pregnancy both hypoxic and oxidative stress occur concomitantly60 and stimulate HIF1α function61. The increased expression of Hif1α in embryos developing during diabetic pregnancies provides a defence mechanism to protect them from the toxic effects of glucose16, 41. Although ALX3 does not appear to regulate Hif1α directly, our data support the notion that the stimulated increase of ALX3 in response to elevated glucose levels plays an important role to coordinate the protective response of the embryo to maternal diabetes because Alx3-deficiency significantly impairs the enhanced expression of embryonic Hif1α and oxidative stress detoxifying genes during diabetic pregnancy.