Fatal bilateral chylothorax in mice lacking the integrin α9β1

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 alpha 9 beta 1 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 alpha 9 beta 1, we have generated mice lacking expression of the alpha 9 subunit. Mice homozygous for a null mutation in the alpha 9 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. alpha 9(-/-) mice also develop edema and lymphocytic infiltration in the chest wall that appears to originate around lymphatics. alpha 9 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 alpha 9 integrin is required for the normal development of the lymphatic system, including the thoracic duct, and that alpha 9 deficiency could be one cause of congenital chylothorax.