Fatal Bilateral Chylothorax in Mice Lacking the Integrin a9b1

Members of the integrin family of adhesion receptors mediate both cell-cell and cell-matrix interactions and have been shown to play vital roles in embryonic development, wound healing, metastasis, and other biological processes. The integrin a9b1 is a receptor for the extracellular matrix proteins osteopontin and tenacsin C and the cell surface immunoglobulin vascular cell adhesion molecule-1. This receptor is widely expressed in smooth muscle, hepatocytes, and some epithelia. To examine the in vivo function of a9b1, we have generated mice lacking expression of the a9 subunit. Mice homozygous for a null mutation in the a9 subunit gene appear normal at birth but develop respiratory failure and die between 6 and 12 days of age. The respiratory failure is caused by an accumulation of large volumes of pleural fluid which is rich in triglyceride, cholesterol, and lymphocytes. a9 mice also develop edema and lymphocytic infiltration in the chest wall that appears to originate around lymphatics. a9 protein is transiently expressed in the developing thoracic duct at embryonic day 14, but expression is rapidly lost during later stages of development. Our results suggest that the a9 integrin is required for the normal development of the lymphatic system, including the thoracic duct, and that a9 deficiency could be one cause of congenital chylothorax.