Rac it up!

Rac it up! The Rho guanosine triphosphatases (GTPases), including Rho, Rac, and Cdc42, are a family of molecules involved in regulating cellular function, but the specific members critically involved in hematopoeitic cells have not been established. In this report, the investigators generated mice that were conditionally deficient in Rac1, Rac2, or both Rac1 and Rac2 (only in hematopoeitic cells) and focused on the function of blood cells. The absence of Rac1 was associated with an impressive reduction in the ability of hematopoietic stem cell/progenitor (HSC/Ps) to engraft immunodeficient mice. In the absence of both Rac1 and Rac2 there was a massive mobilization of progenitor colony-forming unit cells into the circulation by a mechanism likely dependent on impaired integrin-mediated stem cell adhesion. Both molecules were found to contribute to HSC/Ps growth and migration to stromal-derived factor 1. Rac1 was found to have a relatively larger contribution in regulating cell cycle progression, whereas Rac2 was found to preferentially regulate HSC/Ps apoptosis and actin assembly (cytoskeleton rearrangement). Finally, the authors generated neutrophils from HSC/Ps and demonstrated that these mature cells had similar dependence on both Racs, including a cooperative role in regulating oxidase activity. Collectively, these elegant investigations demonstrate that Rac1 and Rac2 regulate unique aspects of hematopoieitic development and function. The studies provide a mechanistic basis to explain a potential diverse set of immunodeficiency syndromes caused by Rac mutations in patients. Indeed, Rac2 mutations have already been associated with recurrent bacterial infections in select patients. (Gu Y et al. Science 2003;302:445-9.)

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March 2004

J ALLERGY CLIN IMMUNOL