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

Abstract

Cell migration is a fundamental biological process involving membrane polarization and cytoskeletal dynamics1, both of which are regulated by Rho family GTPases2,3,4,5. Among these molecules, Rac is crucial for generating the actin-rich lamellipodial protrusion, a principal part of the driving force for movement3,6. 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 Rac7,8,9,10,11,12. Although genetic analysis has shown that CED-5 and Myoblast City are crucial for migration of particular types of cells8,9,12, physiological relevance of the CDM family proteins in mammals remains unknown. Here we show that DOCK2, a haematopoietic cell-specific CDM family protein13, is indispensable for lymphocyte chemotaxis. DOCK2-deficient 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.

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Figure 1: Remodelling of actin cytoskeleton by DOCK2 in a T-cell line.
Figure 2: Impaired homing of DOCK2-/- lymphocytes into secondary lymphoid organs.
Figure 3: Lymphocyte migration defect in DOCK2-/- mice.
Figure 4: Abnormal architecture of the immune system in DOCK2-/- mice.

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Acknowledgements

We thank K. Matsushima and N. Onai for anti-CXCR4 and anti-CCR7 antibodies; K.-i. Nakayama and K. Nakayama for E14 ES cells and helpful suggestions on ES cell culture; P. Marrack for BEα16-3; and Y. Yamada for blastocyst injection. This work was supported in part by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Correspondence to Toshikazu Shirai.

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Fukui, Y., Hashimoto, O., Sanui, T. et al. Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration. Nature 412, 826–831 (2001). https://doi.org/10.1038/35090591

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