Rac GTPases play critical roles in early T-cell development.
The Rac1 and Rac2 GTPases play important roles in many processes including cytoskeletal reorganization, proliferation, and survival, and are required for B-cell development. Previous studies had shown that deficiency in Rac2 did not affect T-cell development, whereas the function of Rac1 in this process has not been investigated. We now show that simultaneous absence of both GTPases resulted in a very strong developmental block at the pre-TCR checkpoint and in defective positive selection. Unexpectedly, deficiency of Rac1 and Rac2 also resulted in the aberrant survival of thymocytes lacking expression of TCR beta, showing hallmarks of hyperactive Notch signaling. Furthermore, we found a similar novel phenotype in the absence of Vav1, Vav2, and Vav3, which function as guanine nucleotide exchange factors for Rac1 and Rac2. These results show that a pathway containing Vav and Rac proteins may negatively regulate Notch signaling during early thymic development.
Dumont
Celine
C
Division of Immune Cell Biology, Medical Research Council (MRC) National Institute for Medical Research, London, UK.
Corsoni-Tadrzak
Agnieszka
A
Ruf
Sandra
S
de Boer
Jasper
J
Williams
Adam
A
Turner
Martin
M
Kioussis
Dimitris
D
Tybulewicz
Victor L J
VL
D000818:Animals; D049109:Cell Proliferation; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism; D019891:Leukopoiesis / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D013950:Thymus Gland / Q000201:enzymology / Q000276:immunology; D013997:Time Factors; D046509:Tissue Culture Techniques; D020744:rac GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein
D015851:Interleukin-7; D009479:Neuropeptides; D011948:Receptors, Antigen, T-Cell; D051880:Receptors, Notch; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C484602:Rac1 protein, mouse