Cell adhesion events mediated by α4 integrins are essential in placental and cardiac development

Abstract

α4 integrins are cell surface receptors that mediate cell-extracellular matrix (ECM) and cell-cell adhesions by interacting with fibronectin (FN) and vascular cell adhesion molecule 1 (VCAM-1), respectively. We have generated a null mutation in the gene for the α4 integrin subunit. Homozygous null embryos express no α4 integrins and show two unexpected defects, both of which lead to embryonic lethality. The first defect is failure of fusion of the allantois with the chorion during placentation. The second is in the development of the epicardium and coronary vessels leading to cardiac hemorrhrage. Both processes clearly involve α4 integrin interactions that were previously unsuspected. α4 integrin and VCAM-1 are expressed at the sites of these interactions. These results raise the possibility of abortifacients targeting α4 integrins, and raise serious questions about potential side effects of drugs currently being designed to block α4 integrin functions in inflammation.