The GTPase Rho has a critical regulatory role in thymus development.
The present study employs a genetic approach to explore the role of Rho GTPases in murine thymic development. Inactivation of Rho function in the thymus was achieved by thymic targeting of a transgene encoding C3 transferase from Clostridium botulinum which selectively ADP-ribosylates Rho within its effector domain and thereby abolishes its biological function. Thymi lacking functional Rho isolated from C3 transgenic mice were strikingly smaller and showed a marked (90%) decrease in cellularity compared with their normal litter mates. We also observed a similar decrease in levels of peripheral T cells in C3 transgenic mice. Analysis of the maturation status of thymocytes indicated that differentiation of progenitor cells to mature T cells can occur in the absence of Rho function, and both positive and negative selection of T cells appear to be intact. However, transgenic mice that lack Rho function in the thymus show maturational, proliferative and cell survival defects during T-cell development that severely impair the generation of normal numbers of thymocytes and mature peripheral T cells. The present study thus identifies a role for Rho-dependent signalling pathways in thymocyte development. The data show that the function of Rho GTPases is critical for the proliferative expansion of thymocytes. This defines a selective role for the GTPase Rho in early thymic development as a critical integrator of proliferation and cell survival signals.
Henning
S W
SW
Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London, UK. henning@europa.lif.icnet.uk
Galandrini
R
R
Hall
A
A
Cantrell
D A
DA
D036002:ADP Ribose Transferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001905:Botulinum Toxins; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002453:Cell Cycle; D002454:Cell Differentiation; D003014:Clostridium botulinum / Q000201:enzymology; D005260:Female; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D020690:GTPase-Activating Proteins; D006182:H-Y Antigen / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development*; D019076:Transgenes
D020690:GTPase-Activating Proteins; D006182:H-Y Antigen; D011948:Receptors, Antigen, T-Cell; C085379:rho GTPase-activating protein; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D001905:Botulinum Toxins; D019204:GTP-Binding Proteins