TISSUE-SPECIFIC RESCUE SUGGESTS THAT PLACENTAL ADENOSINE-DEAMINASE ISIMPORTANT FOR FETAL DEVELOPMENT IN MICE

Adenosine deaminase (ADA, EC 3.5.4.4) is an essential enzyme of purine metabolism that is expressed at very high levels in the murine placen ta where it accounts for over 95% of the ADA present at the fetal gest ation site. We have recently shown that ADA-deficient fetuses, which a lso lack ADA in their adjoining placentas, die during late fetal devel opment in association with profound purine metabolic disturbances and hepatocellular impairment. We have now investigated the potential impo rtance of placental ADA by genetically restoring the enzyme to placent as of ADA-deficient fetuses. This genetic engineering strategy correct ed most of the purine metabolic disturbances, prevented serious fetal liver damage, and rescued the fetuses from perinatal lethality. Our fi ndings suggest that placental ADA is important for murine fetal develo pment and illustrate a general strategy for the tissue specific correc tion of phenotypes associated with null mutations in mice.