Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III

Abstract

Single gene mutations in β integrins can account for functional defects of individual cells of the hematopoietic system. In humans, mutations in β₂ integrin lead to leukocyte adhesion deficiency (LAD) syndrome and mutations in β₃ integrin cause the bleeding disorder Glanzmann thrombasthenia. However, multiple defects in blood cells involving various β integrins (β₁, β₂, and β₃) occur simultaneously in patients with the recently described LAD type III (LAD-III). Here we show that the product of a single gene, Ca²⁺ and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), controlled the activation of all 3 integrins in the hematopoietic system. Neutrophils from CalDAG-GEFI^–/– mice exhibited strong defects in Rap1 and β₁ and β₂ integrin activation while maintaining normal calcium flux, degranulation, and ROS generation. Neutrophils from CalDAG-GEFI–deficient mice failed to adhere firmly to stimulated venules and to migrate into sites of inflammation. Furthermore, CalDAG-GEFI regulated the activation of β₁ and β₃ integrins in platelets, and CalDAG-GEFI deficiency caused complete inhibition of arterial thrombus formation in mice. Thus, mice engineered to lack CalDAG-GEFI have a combination of defects in leukocyte and platelet functions similar to that of LAD-III patients.