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Rac-King up New Roles in Haematopoiesis

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HIGHLIGHTS numbers of pro-B, pre-B and imma- SIGNALLING IN BRIEF ture B cells in the bone marrow, but reduced numbers of B cells at later Rac-king up developmental stages in the spleen NATURAL KILLER CELLS and lymph nodes. In the absence of new roles in both Rac1 and Rac2, B-cell develop- The mature activating natural killer cell immunologic ment seems to be blocked at the synapse is formed in distinct stages. haematopoiesis transitional type 1 B-cell stage in the Orange, J. S. et al. Proc. Natl Acad. Sci. USA 100, 14151–14156 (2003) spleen. Rac1 and Rac2 guanosine triphos- Recent studies have shown activa- The interface between a natural killer (NK) cell and its target cell phatases (GTPases) are crucial sig- tion of Rac1 after B-cell receptor — the activating NK-cell immunological synapse — is highly nalling regulators in eukaryotic (BCR) stimulation, and signals from organized. In this study, Orange et al. show that CD2 and CD11b, cells, acting downstream of various the BCR are known to be crucial for similar to CD11a, co-localize with filamentous actin in the cellular receptors. Two studies pub- B-cell development, so are BCR sig- peripheral supramolecular activation cluster (pSMAC), whereas lished in Science have used condi- nalling defects responsible for the perforin accumulates in the central SMAC (cSMAC). Polarization tional gene targeting to clarify the observed phenotype of Rac1BRac2–/– of CD2, CD11a and CD11b to the pSMAC was dependent on roles of Rac1 and Rac2 in particular mice? Rac2–/– and Rac1–/+Rac2–/– actin polymerization and Wiskott-Aldrich syndrome protein aspects of haematopoietic-cell mature B cells stimulated with an (WASP), but independent of microtubule function. By contrast, differentiation. IgM-specific antibody had decreased perforin accumulation in the cSMAC was dependent on actin Gu et al. looked at the differential survival compared with wild-type polymerization, WASP and microtubule function. In addition, activity of Rac1 and Rac2 in B cells, which correlated with the rate of cSMAC perforin accumulation was slower than the haematopoietic stem/progenitor cells decreased induction of the anti- recruitment of receptors to the pSMAC, indicating that formation of the NK-cell immunological synapse is a highly regulated, (HSC/Ps). As Rac1 deficiency is apoptotic protein Bcl-XL.These embryonic lethal, they generated B cells also proliferated less than sequential process. conditional Rac1-knockout mice. wild-type cells. This was shown to be Deficiency of Rac1 inhibited the due to decreased induction of the MUCOSAL IMMUNOLOGY ability of HSC/Ps to reconstitute cell-cycle regulator cyclin D2 after haematopoiesis in an engraftment stimulation. So, Rac1 and Rac2 Spheniscins: avian β-defensins in preserved stomach model (which requires adhesion and transduce BCR signals for B-cell sur- contents of the king penguin, Aptenodytes proliferation in the bone marrow), vival and entry into the cell cycle. patagonicus. and the absence of both Rac1 and Finally, in contrast to wild-type cells, Thouzeau, C. et al. J. Biol. Chem. 2 October 2003 (doi:10.1074/jbc.M306839200) Rac2 led to the movement of progen- BAFF could not increase the survival In this paper, Thouzeau and colleagues have identified two new itor cells out of the bone marrow and of Rac1BRac2–/– immature B cells, avian antimicrobial peptides in the stomach of the male king into the peripheral circulation, as a and this was probably the result of penguin. These peptides, known as spheniscin 1 and 2, belong result of decreased adhesion to decreased expression of BAFF recep- to the β-defensin family and have broad antimicrobial activity fibronectin. Rac1 and Rac2 were also tor (BAFFR). Rac1 and Rac2 were against pathogenic bacteria and fungi. The levels of spheniscin shown to have roles in regulating the shown to transduce BCR signals lead- 1 and 2 are higher during periods of food storage than when cytoskeletal changes that are required ing to the upregulation of expression the birds are digesting, and interestingly, a drop in spheniscin for engraftment and mobilization. of BAFFR messenger RNA. levels correlated with a change from food storage to digestion. Rac1–/–, and to a greater extent These two studies show that in These antimicrobial peptides act to protect the surface of the Rac1–/–Rac2–/–, HSC/Ps had reduced both B cells and HSC/Ps, Rac1 and bird’s gastrointestinal tract from damage or invasion, and proliferation in response to growth Rac2 have essential roles in control- might be important for the long-term preservation of stored factors in vitro,correlating with ling proliferation and survival. food, which can be important for chick survival. decreased levels of cyclin D1 and Furthermore, despite their sequence phosphorylation of extracellular similarity, the two GTPases seem to signal-regulated kinase (ERK), and have partially non-redundant physi- increased levels of the cyclin- ological functions. Gu et al.con- dependent kinase inhibitor KIP1. By firmed this functional distinction in contrast, Rac2–/– cells were more sus- neutrophils, in which Rac2 seems to ceptible to apoptosis after growth- be the main GTPase regulating factor stimulation, associated with directed migration and superoxide reduced Akt activation. Therefore, it generation, whereas Rac1 regulates seems that Rac1 regulates entry into neutrophil shape. the cell cycle, whereas Rac2 mainly Kirsty Minton regulates cell survival. Walmsley et al.looked further References and links ORIGINAL RESEARCH PAPERS Gu, Y. et al. downstream at B-cell development Hematopoietic cell regulation by Rac1 and Rac2 by generating, for the first time, mice guanosine triphosphatases. Science 302, with a conditional deletion of Rac1 445–449 (2003) | Walmsley, M. J. et al. Critical B roles for Rac1 and Rac2 GTPases in B cell in the B-cell lineage (Rac1 mice). development and signaling. Science 302, Rac1BRac2–/– mice had normal 459–462 (2003) NATURE REVIEWS | IMMUNOLOGY VOLUME 3 | DECEMBER 2003 | 925.
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