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and 
1
* Department of Molecular Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan;
KAN Research Institute, Kyoto, Japan;
Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan; and
Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita, Japan
Rho family small GTP-binding proteins, including Rho, Rac, and Cdc42, are key determinants of cell movement and actin-dependent cytoskeletal morphogenesis. Rho GDP-dissociation inhibitor (GDI) 
and Rho GDI
(or D4/Ly-GDI), closely related regulators for Rho proteins, are both expressed in hemopoietic cell lineages. Nevertheless, the functional contributions of Rho GDIs remain poorly understood in vivo. In this study, we report that combined disruption of both the Rho GDI and Rho GDI genes in mice resulted in reduction of marginal zone B cells in the spleen, retention of mature T cells in the thymic medulla, and a marked increase in eosinophil numbers. Furthermore, these mice showed lower CD3 expression and impaired CD3-mediated proliferation of T cells. While B cells showed slightly enhanced chemotactic migration in response to CXCL12, peripheral T cells showed markedly reduced chemotactic migration in response to CCL21 and CCL19 associated with decreased receptor levels of CCR7. Overall, Rho protein levels were reduced in the bone marrow, spleen, and thymus but sustained activation of the residual part of RhoA, Rac1, and Cdc42 was detected mainly in the bone marrow and spleen. Rho GDI and Rho GDI thus play synergistic roles in lymphocyte migration and development by modulating activation cycle of the Rho proteins in a lymphoid organ-specific manner.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a Grant-In-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grants 14028074, 15024275, 16022268, and 17014090; to J.M.).
2 Address correspondence and reprint requests to Dr. Jun Miyoshi, Department of Molecular Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Nakamichi 1-3-2, Higashinari-ku, Osaka 537-8511, Japan. E-mail address: miyosi-ju{at}mc.pref.osaka.jp
3 Abbreviations used in this paper: GDI, GDP-dissociation inhibitor; WT, wild type; BM, bone marrow; NF, newly formed; T1, transitional 1; T2, transitional 2; FO, follicular; MZ, marginal zone; MLN, mesenteric lymph node; DN, double negative; DP, double positive; SP, single positive; TXA, thromboxane A.
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