The Rho GTPase Cdc42 is essential for B lyphocyte development and Activation

Cdc42 of the Rho GTPase family has been implicated in a wide range of fundamental cell functions including actin cytoskeleton dynamics, proliferation, and migration, but its cell-type specific functions have just begun to be appreciated. Previous studies of Cdc42 in B cell regulation by using dominant mutant forms of Cdc42 suggest that Cdc42 is involved in B cell cytoskeleton organization and antigen-receptor signaling, however, its contribution to the B-lineage development and B cell physiology remains unknown. In this study we have achieved B cell- and hematopoietic stem cell-deletion of cdc42 by conditional gene targeting with the CD19 and Mx promoter-driven Cre expression, respectively, in the cdc42^loxP/loxP mice. Deletion of cdc42 after the pre-proB cell stage significantly inhibited late B cell development, resulting in reduced mature B cell populations in spleen, bone marrow, peripheral blood, lymph node, and peritoneal cavity. Accordingly, antigen-specific IgM, IgG1 and IgG3, was reduced in the Cdc42-deificient mice. The reduction of Cdc42 knockout B cells are associated with impaired proliferation and survival. Cdc42 deficiency caused a BCR signaling defect with increased Erk and decreased Akt activation, and a defect in BCR-mediated BAFF receptor upregulation and subsequent BAFF receptor signaling in the mature resting B cells. Interestingly, Cdc42 is dispensable for SDF-1α- or BLC-induced B cell migration. Further, deletion of Cdc42 from hematopoietic stem cells resulted in an unaltered common lymphoid progenitor production but severely reduced pre-proB/proB/preB and immature B cell populations, indicating that Cdc42 is also critically involved in the B cell precursor differentiation. Together our results reveal multi-facet roles of Cdc42 in B cell development and activation.