Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration

Cell migration is a fundamental biological process involving membrane polarization and cytoskeletal dynamics(1), both of which are regulated by Rho family GTPases(2-5). Among these molecules, Rac is crucial for generating the actin-rich lamellipodial protrusion, a principal part of the driving force for movement(3,6). The CDM family proteins, Caenorhabditis elegans CED-5, human DOCK180 and Drosophila melanogaster Myoblast City (MBC), are implicated to mediate membrane extension by functioning upstream of Rac(7-12). Although genetic analysis has shown that CED-5 and Myoblast City are crucial for migration of particular types of cells(8,9,12), physiological relevance of the CDM family proteins in mammals remains unknown. Here we show that DOCK2, a haematopoietic cell-specific CDM family protein(13), is indispensable for lymphocyte chemotaxis. DOCK2-dercient mice (DOCK2(-/-)) exhibited migration defects of T and B lymphocytes, but not of monocytes, in response to chemokines, resulting in several abnormalities including T lymphocytopenia, atrophy of lymphoid follicles and loss of marginal-zone B cells. In DOCK2(-/-) lymphocytes, chemokine-induced Rac activation and actin polymerization were almost totally abolished. Thus, in lymphocyte migration DOCK2 functions as a central regulator that mediates cytoskeletal reorganization through Rac activation.