CELL-ADHESION EVENTS MEDIATED BY ALPHA(4) INTEGRINS ARE ESSENTIAL IN PLACENTAL AND CARDIAC DEVELOPMENT

alpha(4) integrins are cell surface receptors that mediate cell-extrac ellular matrix (ECM) and cell-cell adhesions by interacting with fibro nectin (FN) and vascular cell adhesion molecule 1 (VCAM-1), respective ly. We have generated a null mutation in the gene for the alpha(4) int egrin subunit. Homozygous null embryos express no alpha(4) integrins a nd show two unexpected defects, both of which lead to embryonic lethal ity. The first defect is failure of fusion of the allantois with the c horion during placentation. The second is in the development of the ep icardium and coronary vessels leading to cardiac hemorrhrage. Both pro cesses clearly involve alpha(4) integrin interactions that were previo usly unsuspected. alpha(4) integrin and VCAM-1 are expressed at the si tes of these interactions. These results raise the possibility of abor tifacients targeting alpha(4) integrins, and raise serious questions a bout potential side effects of drugs currently being designed to block alpha(4) integrin functions in inflammation.