Rac1 is the small GTPase Responsible for Regulating the Neutrophil Chemotaxis Compass Short running title: Rac1 Regulates Neutrophil Chemotaxis Compass

Although both of the small Rho GTPases Rac1 and Rac2 have been demonstrated to play a role in chemotaxis, the precise and possible unique roles performed by each of these two Rac isoforms in neutrophil chemotaxis have not been defined. To elucidate the specific roles of Rac 1 and Rac 2 in neutrophils during the process of chemotaxis, we generated mice deficient in Rac1, Rac2, or in both Rac1 and 2 in cells of myeloid lineage including neutrophils by mating Rac 2 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 while Rac1 null neutrophils display normal chemokinesis, they are unable to migrate towards the source of the chemoattractant. By contrast, Rac2 null neutrophils can orient towards the chemoattractant source but are unable to migrate efficiently. We show that Rac1 is essential for gradient detection and orientation towards the chemoattractant source through spatially constrained regulation of 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. For personal use only. by guest on June 7, 2013. bloodjournal.hematologylibrary.org From