title: Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in T-cell development.
abstract: Rac GTPases have been implicated in the regulation of diverse functions in various blood cell lineages, but their role in T-cell development is not well understood. We have carried out conditional gene targeting to achieve hematopoietic stem cell (HSC)- or T-cell lineage-specific deletion of Rac1 or Rac1/Rac2 by crossbreeding the Mx-Cre or Lck-Cre transgenic mice with Rac1(loxp/loxp) or Rac1(loxp/loxp);Rac2(-/-) mice. We found that (1) HSC deletion of both Rac1 and Rac2 inhibited production of common lymphoid progenitors (CLPs) in bone marrow and suppressed T-cell development in thymus and peripheral organs, whereas deletion of Rac1 moderately affected CLP production and T-cell development. (2) T cell-specific deletion of Rac1 did not affect T-cell development, whereas deletion of both Rac1 and Rac2 reduced immature CD4(+)CD8(+) and mature CD4(+) populations in thymus as well as CD4(+) and CD8(+) populations in spleen. (3) The developmental defects of Rac1/Rac2 knockout T cells were associated with proliferation, survival, adhesion, and migration defects. (4) Rac1/Rac2 deletion suppressed T-cell receptor-mediated proliferation, IL-2 production, and Akt activation in thymocytes. Thus, Rac1 and Rac2 have unique roles in CLP production and share a redundant but essential role in later stages of T-cell development by regulating survival and proliferation signals.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, OH, USA.
authors.forename: Fukun
authors.initials: F
authors.lastname: Guo
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cancelas
authors.forename: David
authors.initials: D
authors.lastname: Hildeman
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D018390:Gene Targeting; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis; D038041:Lymphopoiesis / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D020744:rac GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein
chemical_list: D007376:Interleukin-2; D009479:Neuropeptides; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C484602:Rac1 protein, mouse