The GTPase Rho has a critical regulatory role in thymus development

• Published in: The EMBO journal Vol. 16; no. 9; pp. 2397 - 2407
• Main Authors: Henning, Stefan W., Galandrini, Ricciarda, Hall, Alan, Cantrell, Doreen A.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.05.1997
• Subjects: ADP Ribose Transferases - genetics; ADP Ribose Transferases - metabolism; Animals; Apoptosis; Botulinum Toxins; C3 transferase; CD4-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - cytology; Cell Cycle; Cell Differentiation; Clostridium botulinum - enzymology; development; Female; GTP-Binding Proteins - antagonists & inhibitors; GTP-Binding Proteins - physiology; GTPase; GTPase-Activating Proteins; H-Y Antigen - genetics; H-Y Antigen - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Rho; thymus; Thymus Gland - cytology; Thymus Gland - growth & development; Transgenes
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1093/emboj/16.9.2397

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.