Defective chemokine-directed lymphocyte migration and development in the absence of Rho guanosine diphosphate-dissociation inhibitors alpha and beta.
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) alpha and Rho GDIbeta (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 GDIalpha and Rho GDIbeta 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 GDIalpha and Rho GDIbeta thus play synergistic roles in lymphocyte migration and development by modulating activation cycle of the Rho proteins in a lymphoid organ-specific manner.
Ishizaki
Hiroyoshi
H
Department of Molecular Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Nakamichi 1-3-2, Higashinari-ku, Osaka 537-8511, Japan.
Togawa
Atsushi
A
Tanaka-Okamoto
Miki
M
Hori
Keiko
K
Nishimura
Miyuki
M
Hamaguchi
Akiko
A
Imai
Toshio
T
Takai
Yoshimi
Y
Miyoshi
Jun
J
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002452:Cell Count; D002478:Cells, Cultured; D002633:Chemotaxis; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism / Q000502:physiology*; D008198:Lymph Nodes / Q000166:cytology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015778:Minor Histocompatibility Antigens; D009928:Organ Specificity; D011506:Proteins / Q000502:physiology*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
C569639:Arhgdia protein, mouse; C569659:Arhgdib protein, mouse; D020730:Guanine Nucleotide Dissociation Inhibitors; D015778:Minor Histocompatibility Antigens; D011506:Proteins; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D020741:rho GTP-Binding Proteins