title: Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III.
abstract: Single gene mutations in beta integrins can account for functional defects of individual cells of the hematopoietic system. In humans, mutations in beta(2) integrin lead to leukocyte adhesion deficiency (LAD) syndrome and mutations in beta(3) integrin cause the bleeding disorder Glanzmann thrombasthenia. However, multiple defects in blood cells involving various beta integrins (beta(1), beta(2), and beta(3)) occur simultaneously in patients with the recently described LAD type III (LAD-III). Here we show that the product of a single gene, Ca(2+) 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 beta(1) and beta(2) 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 beta(1) and beta(3) 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.
authors.affiliation: CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA. bergmeier@cbrinstitute.org
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bergmeier
authors.forename: Tobias
authors.initials: T
authors.lastname: Goerge
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Wang
authors.forename: Jill R
authors.initials: JR
authors.lastname: Crittenden
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Baldwin
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Cifuni
authors.forename: David E
authors.initials: DE
authors.lastname: Housman
authors.forename: Ann M
authors.initials: AM
authors.lastname: Graybiel
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism; D004195:Disease Models, Animal; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D019012:Integrin beta1 / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D015539:Platelet Activation; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D018821:CD18 Antigens; D020662:Guanine Nucleotide Exchange Factors; D019012:Integrin beta1; D039661:Integrin beta3; C485927:Rasgrp2 protein, mouse; D020827:rap1 GTP-Binding Proteins