Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment

Wang, Lei; Yang, Linda; Filippi, Marie–Dominique; Williams, David A.; Zheng, Yi

doi:10.1182/blood-2005-05-2171

Cited by 82 publications

(99 citation statements)

References 34 publications

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“…Together with previous characterization of the hematopoietic properties of a Cdc42 gain-of-activity Cdc42GAP knockout mouse model (13), these results suggest that Cdc42 activity represents a critical regulator and coordinator of external and intrinsic cues that control microanatomical location, interaction with the surrounding microenvironment, and cell cycle induction of HSCs.…”

Section: Resultssupporting

confidence: 77%

“…The current Cdc42 conditional knockout model reveals unique HSC regulatory functions of Cdc42 that are not predictable in the Cdc42 gain-of-activity Cdc42GAP Ϫ/Ϫ mice (13,23,24). Although Cdc42GAP Ϫ/Ϫ hematopoietic progenitors show normal cell cycle progression but increased apoptosis due to increased JNK activity, Cdc42 Ϫ/Ϫ HSCs display drastically increased cell cycle progression/entry but unaltered survival property.…”

Section: Resultsmentioning

confidence: 92%

“…Although its function has been extensively studied in various cell systems by expression of dominant negative or constitutively active mutants (12), the physiological roles of Cdc42 in most primary cell lineages, particularly in HSCs, remain unclear. Previously, in a gain-of-Cdc42 activity, Cdc42GAP Ϫ/Ϫ mouse model, we have found that constitutively increased Cdc42-GTP species cause increased hematopoietic progenitor apoptosis, disorganized actin structure, and defective engraftment without affecting the cell cycle status (13). To further define the role of Cdc42 in HSC regulation, in this study, we present a conditional-knockout mouse model in which the cdc42 gene is inducibly deleted in hematopoietic cells.…”

mentioning

confidence: 98%

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Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow

Yang¹,

Wang²,

Geiger³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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167

164

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Adult hematopoietic stem cells (HSCs) exist in a relatively quiescent state in the bone marrow (BM) microenvironment to fulfill longterm self-renewal and multilineage differentiation functions, an event that is tightly regulated by extrinsic and intrinsic cues. However, the mechanism coordinating the quiescent state of HSCs and their retention in the BM microenvironment remains poorly understood. In a conditional-knockout mouse model, we show that Cdc42 ؊/؊ HSCs enter the active cell cycle, resulting in significantly increased number and frequency of the stem/progenitor cells in the BM. Cdc42 deficiency also causes impaired adhesion, homing, lodging, and retention of HSCs, leading to massive egress of HSCs from BM to distal organs and peripheral blood and to an engraftment failure. These effects are intrinsic to the HSCs and are associated with deregulated c-Myc, p21 Cip1 , ␤1-integrin, and Ncadherin expressions and defective actin organization. Thus, Cdc42 is a critical coordinator of HSC quiescence maintenance and interaction with the BM niche.bone marrow microenvironment ͉ cell cycle ͉ adhesion A dult hematopoietic stem cells (HSCs) exist in a relatively quiescent state in the bone marrow (BM) microenvironment to execute long-term self-renewal and multilineage differentiation functions (1-3). The maintenance of HSC quiescence involves both extrinsic and intrinsic mechanisms. A number of genes that encode cell cycle or transcriptional regulators, including p21 Cip1 , p27 Kip1 , ␤-catenin/axin, cyclin D1, and c-Myc (4, 5), have been shown to regulate the intrinsic programs of HSCs in this process. In addition, interactions of HSCs with the BM microenvironment in specific anatomical and functional areas, referred to as niches, in the maintenance of HSC quiescence have also gained increasing recognition (6). One hypothesis is that the intrinsic and extrinsic cues, such as bone morphogenic proteins, Ca 2ϩ , Notch ligands, and/or Ang-1/Tie2 (7-10), in the BM microenvironment may coordinately regulate the HSC quiescent state.Despite of the identification of these molecular factors in HSCs and in BM that may collectively contribute to the maintenance of quiescence (7), the mechanism coordinating HSC cell cycle regulation and niche interaction remains unclear. Cdc42 is a ubiquitously expressed member of the Rho GTPase family involved in the regulation of multiple cell functions, including actin polymerization, cell-to-cell or cell-to-extracellular matrix adhesion, and gene transcription (11). Although its function has been extensively studied in various cell systems by expression of dominant negative or constitutively active mutants (12), the physiological roles of Cdc42 in most primary cell lineages, particularly in HSCs, remain unclear. Previously, in a gain-of-Cdc42 activity, Cdc42GAP Ϫ/Ϫ mouse model, we have found that constitutively increased Cdc42-GTP species cause increased hematopoietic progenitor apoptosis, disorganized actin structure, and defective engraftment without affecting the cell cycle status (13). T...

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Section: Resultssupporting

confidence: 77%

Section: Resultsmentioning

confidence: 92%

mentioning

confidence: 98%

See 1 more Smart Citation

Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow

Yang¹,

Wang²,

Geiger³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

167

164

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“…Interestingly, those few studies commonly reported that the ablation of a specific GAP resulted in the global elevation of the activity of the target small GTPase (49,57,58); Rho GTP levels were highly elevated in P190B RhoGAP null murine embryonic fibroblasts (49), as was the Cdc42 GTP level in Cdc42GAP null murine embryonic fibroblasts and hematopoietic stem cells (57,58). Those studies also reported changes in the overall size of the cells or the whole animal as well as in the growth of cells (49,57,58). However, we did not see any difference in basal Rac GTP levels among bcr Ϫ/Ϫ , abr Ϫ/Ϫ , and (abr ϫ bcr) Ϫ/Ϫ BMMs, nor did we observe any change in the overall cell size of BMMs or the whole animal (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Abr and Bcr, Two Homologous Rac GTPase-Activating Proteins, Control Multiple Cellular Functions of Murine Macrophages

Cho

Cunnick²,

Yi³

et al. 2007

Molecular and Cellular Biology

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“…To clarify the function of mammalian Cdc42, we have generated Cdc42 conditional knockout mice by a loxP/ Cre recombination strategy to allow controlled deletion of Cdc42 in primary cells, as well as a Cdc42 gain-of-activity mouse model by gene targeting of a negative regulator of Cdc42, Cdc42GAP, that leads to specific upregulation of endogenous Cdc42 activity in most cell types (Wang et al, , 2006. We report here the results obtained from the Cdc42-deficient and Cdc42GAP-deficient primary mouse embryonic fibroblasts (MEFs), which provide genetic evidence implicating Cdc42 in primary cell actin structural organization, migration, and proliferation.…”

Section: Introductionmentioning

confidence: 99%

Gene Targeting of Cdc42 and Cdc42GAP Affirms the Critical Involvement of Cdc42 in Filopodia Induction, Directed Migration, and Proliferation in Primary Mouse Embryonic Fibroblasts

Yang

Wang

Zheng

2006

MBoC

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129

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Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment

Cited by 82 publications

References 34 publications

Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow

Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow

Abr and Bcr, Two Homologous Rac GTPase-Activating Proteins, Control Multiple Cellular Functions of Murine Macrophages

Gene Targeting of Cdc42 and Cdc42GAP Affirms the Critical Involvement of Cdc42 in Filopodia Induction, Directed Migration, and Proliferation in Primary Mouse Embryonic Fibroblasts

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