ENHANCED APOPTOSIS IN THE THYMUS OF TRANSGENIC MICE EXPRESSING CONSTITUTIVELY ACTIVATED FORMS OF HUMAN RAC2GTPASE

Rac proteins constitute a subgroup of the Rho family of small GTPases and include Rac1, which is expressed ubiquitously, and Rac2, a highly homologous protein only expressed in myelo-monocytic and lymphoid cell lineages. In fibroblasts, Rad plays a crucial role in control of acti n cytoskeleton organisation, cell growth and Ras-induced transformatio n. In phagocyte, Rac1 and Rac2 regulate a specific enzymatic complex, NADPH oxidase. These multiple functions have been ascribed to Rac prot eins only on the basis of cell culture and in vitro biochemical studie s. To examine the role of Rac2 in vivo in a T cell lineage, we have ex pressed either wild-type or constitutively-activated forms of human Ra c2 (Rac2V12 and Rac2L61) in transgenic mice under control of the thymu s specific lck proximal promoter. We report here a striking atrophy of the thymus in mice expressing even low levels of either of the activa ted mutants of Rac2, while expression of Rac2wt has no effect. This ph enotype is correlated with a marked decrease in the number of double p ositive (CD4 + CD8 +) and single positive (CD4 + CD8 - and CD8 + CD4 - ) thymocytes, Cellular and molecular analyses demonstrate that this de fect is due to an increase in apoptosis among thymocytes. As Rac2 is n ormally expressed in thymocytes and activated T cells, me propose that Rac2 dependent pathways could play an important role in control of gr owth and death of T cells.