title: Rac signaling in osteoblastic cells is required for normal bone development but is dispensable for hematopoietic development.
abstract: Hematopoietic stem cells (HSCs) interact with osteoblastic, stromal, and vascular components of the BM hematopoietic microenvironment (HM) that are required for the maintenance of long-term self-renewal in vivo. Osteoblasts have been reported to be a critical cell type making up the HSC niche in vivo. Rac1 GTPase has been implicated in adhesion, spreading, and differentiation of osteoblast cell lines and is critical for HSC engraftment and retention. Recent data suggest a differential role of GTPases in endosteal/osteoblastic versus perivascular niche function. However, whether Rac signaling pathways are also necessary in the cell-extrinsic control of HSC function within the HM has not been examined. In the present study, genetic and inducible models of Rac deletion were used to demonstrate that Rac depletion causes impaired proliferation and induction of apoptosis in the OP9 cell line and in primary BM stromal cells. Deletion of Rac proteins caused reduced trabecular and cortical long bone growth in vivo. Surprisingly, HSC function and maintenance of hematopoiesis in vivo was preserved despite these substantial cell-extrinsic changes. These data have implications for therapeutic strategies to target Rac signaling in HSC mobilization and in the treatment of leukemia and provide clarification to our evolving concepts of HSC-HM interactions.
authors: Division of Hematology/Oncology, Children's Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: Steven W
authors: SW
authors: Lane
authors: Serena
authors: S
authors: De Vita
authors: Kylie A
authors: KA
authors: Alexander
authors: Ruchan
authors: R
authors: Karaman
authors: Michael D
authors: MD
authors: Milsom
authors: Adrienne M
authors: AM
authors: Dorrance
authors: Amy
authors: A
authors: Purdon
authors: Leeann
authors: L
authors: Louis
authors: Mary L
authors: ML
authors: Bouxsein
authors: David A
authors: DA
authors: Williams
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001846:Bone Development / Q000502:physiology*; D001854:Bone Marrow Cells; D002450:Cell Communication; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000502:physiology; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D017154:Stromal Cells; D055114:X-Ray Microtomography; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein
chemical_list: D009479:Neuropeptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C484602:Rac1 protein, mouse; C498771:Rac3 protein, mouse