Cell migration is a fundamental biological process involving membrane polar
ization and cytoskeletal dynamics(1), both of which are regulated by Rho fa
mily 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 implicat
ed to mediate membrane extension by functioning upstream of Rac(7-12). Alth
ough genetic analysis has shown that CED-5 and Myoblast City are crucial fo
r migration of particular types of cells(8,9,12), physiological relevance o
f the CDM family proteins in mammals remains unknown. Here we show that DOC
K2, a haematopoietic cell-specific CDM family protein(13), is indispensable
for lymphocyte chemotaxis. DOCK2-dercient mice (DOCK2(-/-)) exhibited migr
ation 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 functio
ns as a central regulator that mediates cytoskeletal reorganization through
Rac activation.