SYNPOLYDACTYLY IN MICE WITH A TARGETED DEFICIENCY IN THE HOXD COMPLEX

THE morphogenesis of mammalian digits requires the function of several genes of the HoxD complex during development of limb buds(1-4). Using embryonic stem (ES) cells and a site-specific recombination system (l oxP/Cre), we have induced a deficiency(5,6) that eliminates the produc ts of the Hoxd-13, Hoxd-12 and Hoxd-11 genes simultaneously. A Hoxd-11 /lacz reporter gene replaced the deleted region in order to monitor th e effect of this triple inactivation at the cellular level. Mice homoz ygous for this deficiency showed small digit primordia, a disorganized cartilage pattern and impaired skeletal mass. These alterations are s imilar to the defects seen in a human synpolydactyly(7,8), suggesting that this syndrome, which is associated with a subtle mutation in HOXD 13 (ref. 8), may involve the loss of function of several Herd genes. T hese results indicate the existence of a functional hierarchy among th ese genes and provide us with an animal model to study human digit mal formations.