Cell migration is regulated by the Rho family of GTPases, which control membrane polarization and cytoskeletal dynamics. Activation of one family member, Rac, is crucial for generation of lamellipodia and for cell movement. Although several molecules have been identified which function as guanine nucleotide-exchange factors for Rac, the upstream signalling cascade leading to Rac activation is not well characterized. CDM family proteins might be involved in this cascade. Genetic studies have shown the importance of these proteins in cellular migration in Caenorhabditis elegans and Drosophila melanogaster, but the physiological relevance of these proteins in mammals is unknown. Fukui and colleagues now report in Nature a vital role for DOCK2 — a haematopoietic cell-specific CDM family member — in lymphocyte, but not monocyte, chemotaxis.

To study the physiological role of DOCK2, Fukui and colleagues generated DOCK2−/− mice. The cellularity of secondary lymphoid organs was reduced in the DOCK2−/− mice, although the proportion of monocytes was increased, indicating that lymphocyte homing might be impaired. To investigate the ability of lymphocytes to migrate to lymph nodes or spleen, fluorescently labelled DOCK2−/− and DOCK2+/− CD4+ T cells or B cells were injected into wild-type mice. The migratory capacity of the DOCK2−/− cells was considerably reduced in comparison with the DOCK2+/− cells.

Next, the authors analysed the movement of DOCK2−/− splenic T and B cells in response to several chemokines. Whereas T and B cells from DOCK2+/− mice migrated in response to secondary lymphoid tissue chemokine (SLC), stroma-derived factor 1 (SDF-1) and B-lymphocyte chemoattractant (BLC), DOCK2−/− cells showed no response to these chemokines.

As DOCK2−/− lymphocytes failed to respond to these chemokines in vitro, Fukui and colleagues carried out further analysis of the DOCK2−/− mice to see if the lack of response affected their phenotype. Several abnormalities were identified, including: a defect in the emigration of mature thymocytes from the thymus, abnormal thymus architecture, atrophy of lymphoid follicles in peripheral lymphoid organs and loss of marginal zone B cells in the spleen. Several of these abnormalities were similar to those observed in mice lacking certain chemokine receptors. These results indicate that lymphocyte and myeloid cell migration are regulated by distinct signalling pathways.