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.
Wolfgang Bergmeier, Tobias Goerge, Hong-Wei Wang, Jill R. Crittenden, Andrew C.W. Baldwin, Stephen M. Cifuni, David E. Housman, Ann M. Graybiel, Denisa D. Wagner
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