Article

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

Division of Experimental Hematology, Children's Hospital Medical Center, University of Cincinnati, OH 45229, USA.
Blood (Impact Factor: 10.45). 02/2006; 107(1):98-105. DOI: 10.1182/blood-2005-05-2171
Source: PubMed

ABSTRACT

Rho family GTPases are key signal transducers in cell regulation. Although a body of literature has implicated the Rho family members Rac1 and Rac2 in multiple hematopoietic-cell functions, the role of Cdc42 in hematopoiesis remains unclear. Here we have examined the hematopoietic properties and the hematopoietic stem/progenitor cell (HSP) functions of gene-targeted mice carrying null alleles of cdc42gap, a negative regulator of Cdc42. The Cdc42GAP-/- fetal liver and bone marrow cells showed a 3-fold increase in Cdc42 activity but normal Rac and RhoA activities, indicating that Cdc42GAP knockout resulted in a gain of Cdc42 activity in the hematopoietic tissues. Cdc42GAP-/- mice were anemic. The cellularity of fetal liver and bone marrow, the number and composition percentage of HSPs, and the erythroid blast-forming unit and colony-forming unit (BFU-E/CFU-E) activities were significantly reduced in the homozygous mice. The decrease in HSP number was associated with increased apoptosis of the Cdc42GAP-/- HSPs and the activation of JNK-mediated apoptotic machinery. Moreover, homozygous HSPs showed impaired cortical F-actin assembly, deficiency in adhesion and migration, and defective engraftment. These results provide evidence that Cdc42 activity is important for erythropoiesis and for multiple HSP functions, including survival, adhesion, and engraftment.

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Available from: Marie-Dominique Filippi, Oct 13, 2014
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    • "Extracellular signals, cell–matrix and cell–cell interactions , as well as intrinsic signals generated during the cell cycle, influence the active GTP-bound and inactive GDP-bound forms of CDC42, which, in turn, modulate interactions with various effector proteins, including PAR, PAK, WASP, and SEC, to regulate diverse cellular functions that influence intercellular junctions, directional protein secretion, spindle orientation and cytoskeletal dynamics (Bryant and Mostov, 2008; Jaffe et al., 2008; Rojas et al., 2001; Symons et al., 1996; Zhang et al., 2001). Recent tissuespecific gene targeting studies demonstrated that CDC42 is required for development of the pancreas, central nervous system , liver, eye, skin, bone, blood and immune system (Cappello et al., 2006; Guo et al., 2010; Maillet et al., 2009; Melendez et al., 2011; van Hengel et al., 2008; Wang et al., 2006; Wu et al., 2006). For example, CDC42 is required for de novo tube formation in the pancreas, which, in turn, regulates pancreatic cell differentiation (Kesavan et al., 2009). "

    Full-text · Article · Feb 2013 · Developmental Biology
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    • "Extracellular signals, cell–matrix and cell–cell interactions , as well as intrinsic signals generated during the cell cycle, influence the active GTP-bound and inactive GDP-bound forms of CDC42, which, in turn, modulate interactions with various effector proteins, including PAR, PAK, WASP, and SEC, to regulate diverse cellular functions that influence intercellular junctions, directional protein secretion, spindle orientation and cytoskeletal dynamics (Bryant and Mostov, 2008; Jaffe et al., 2008; Rojas et al., 2001; Symons et al., 1996; Zhang et al., 2001). Recent tissuespecific gene targeting studies demonstrated that CDC42 is required for development of the pancreas, central nervous system , liver, eye, skin, bone, blood and immune system (Cappello et al., 2006; Guo et al., 2010; Maillet et al., 2009; Melendez et al., 2011; van Hengel et al., 2008; Wang et al., 2006; Wu et al., 2006). For example, CDC42 is required for de novo tube formation in the pancreas, which, in turn, regulates pancreatic cell differentiation (Kesavan et al., 2009). "
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    Preview · Article · Dec 2012 · Developmental Biology
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    • "Targets of BCH domain: RhoA [19], Rab5 [89], Rab11 [89], BNIP-Sa [28] [33] ⁄⁄ Binding sites of Nudel has not been mapped [92] (1) GAP for Cdc42 and Rho [77] [81] [83] [85] (2) BCH domain acts as a local modulator to sequester RhoA from inactivation by its adjacent RhoGAP domain [19] (3) Target to endosome via BCH domain and form complex with Rab11 and Rab5 [89] (4) Nudel sequesters Cdc42GAP at the leading edge of the cell to increase active Cdc42 in presence of phosphorylated ERK [92] (5) Promotes cell migration [81] [82] (6) Suppress muscle cell differentiation by inactivating Cdc42 [34] (1) Auto-inhibition [88] (2) Sequestered by BNIP-Sa from inactivating RhoA, leading to cell rounding and caspase-independent apoptosis [33] Implicated in disease: (1) Up-regulated in Waldenstrom macroglobulinemia [79] (2) Homozygous knockout embryo and newborn mice have reduced organ and body size, due to elevated JNKmediated apoptosis [81] [83] [84] BPGAP1 (BCH containing, proline-rich RhoGAP- 1;ARHGAP8) "
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