title: Cdc42 controls vascular network assembly through protein kinase Cι during embryonic vasculogenesis.
abstract: OBJECTIVE
  The goal of this study was to determine the role of Cdc42 in embryonic vasculogenesis and the underlying mechanisms.
  
  
  RESULTS
  By using genetically modified mouse embryonic stem (ES) cells, we demonstrate that ablation of the Rho GTPase Cdc42 blocks vascular network assembly during embryoid body (EB) vasculogenesis without affecting endothelial lineage differentiation. Reexpression of Cdc42 in mutant EBs rescues the mutant phenotype, establishing an essential role for Cdc42 in vasculogenesis. Chimeric analysis revealed that the vascular phenotype is caused by inactivation of Cdc42 in endothelial cells rather than surrounding cells. Endothelial cells isolated from Cdc42-null EBs are defective in directional migration and network assembly. In addition, activation of atypical protein kinase Cι (PKCι) is abolished in Cdc42-null endothelial cells, and PKCι ablation phenocopies the vascular abnormalities of the Cdc42-null EBs. Moreover, the inhibitory phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9 depends on Cdc42 and PKCι, and expression of kinase-dead GSK-3β in Cdc42-null EBs promotes the formation of linear endothelial segments without branches. These results suggest that PKCι and GSK-3β are downstream effectors of Cdc42 during vascular morphogenesis.
  
  
  CONCLUSIONS
  Cdc42 controls vascular network assembly but not endothelial lineage differentiation by activating PKCι during embryonic vasculogenesis.
authors.affiliation: Department of Surgery, Robert Wood Johnson Medical School-University of Medicine and Dentistry of New Jersey, New Brunswick, 08903-0019, USA.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Qi
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Xunwei
authors.initials: X
authors.lastname: Wu
authors.forename: Cord
authors.initials: C
authors.lastname: Brakebusch
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Yaling
authors.initials: Y
authors.lastname: Han
authors.forename: Siobhan A
authors.initials: SA
authors.lastname: Corbett
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Lowry
authors.forename: Alan M
authors.initials: AM
authors.lastname: Graham
authors.forename: Shaohua
authors.initials: S
authors.lastname: Li
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099293:Protein Kinase C-lambda
chemical_list: D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007527:Isoenzymes; D011493:Protein Kinase C; D020764:cdc42 GTP-Binding Protein; D000099293:Protein Kinase C-lambda; C000605507:Gsk3b protein, mouse