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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3758-3765.
Prepublished online as a Blood First Edition Paper on August 12, 2004; DOI 10.1182/blood-2004-03-0781.
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PHAGOCYTES
Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass
Chun Xiang Sun,
Gregory P. Downey,
Fei Zhu,
Adeline L. Y. Koh,
Herman Thang, and
Michael Glogauer
From the Faculty of Dentistry, University of Toronto; and the Division of Respirology, Department of Medicine, University of Toronto and Toronto General Hospital Research Institute of the University Health Network, ON, Canada.
Although both of the small Rho guanosine triphosphatases (GTPases) Rac1 and Rac2 have been demonstrated to play a role in chemotaxis, the precise and possible unique roles performed by each of these 2 Rac isoforms in neutrophil chemotaxis have not been defined. To elucidate the specific roles of Rac1 and Rac2 in neutrophils during the process of chemotaxis, we generated mice deficient in Rac1, Rac2, or in both Rac1 and Rac2 in cells of myeloid lineage including neutrophils by mating Rac2 null mice with mice carrying a conditional allele for Rac1 and expressing the Cre recombinase downstream of a specific myeloid promoter, lysozyme M. We demonstrate here that although Rac1 null neutrophils display normal chemokinesis, they are unable to migrate toward the source of the chemoattractant. By contrast, Rac2 null neutrophils can orient toward the chemoattractant source but are unable to migrate efficiently. We show that Rac1 is essential for gradient detection and orientation toward the chemoattractant source through spatially constrained regulation of phosphoinositol-3,4,5-trisphosphate (PIP3) and Akt in the leading edge and confirm that Rac2 is the primary regulator of actin assembly providing the molecular motor for neutrophil translocation during chemotaxis.
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