title: Lack of endothelial cell survivin causes embryonic defects in angiogenesis, cardiogenesis, and neural tube closure.
abstract: We explored the physiologic role of endothelial cell apoptosis during development by generating mouse embryos lacking the inhibitor of apoptosis protein (IAP) survivin in endothelium. This was accomplished by intercrossing survivin(lox/lox) mice with mice expressing cre recombinase under the control of the endothelial cell specific tie1 promoter (tie1-cre mice). Lack of endothelial cell survivin resulted in embryonic lethality. Mutant embryos had prominent and diffuse hemorrhages from embryonic day 9.5 (E9.5) and died before E13.5. Heart development was strikingly abnormal. Survivin-null endocardial lineage cells could not support normal epithelial-mesenchymal transformation (EMT), resulting in hypoplastic endocardial cushions and in utero heart failure. In addition, 30% of mutant embryos had neural tube closure defects (NTDs) that were not caused by bleeding or growth retardation, but were likely due to alterations in the release of soluble factors from endothelial cells that otherwise support neural stem cell proliferation and neurulation. Thus, regulation of endothelial cell survival, and maintenance of vascular integrity by survivin are crucial for normal embryonic angiogenesis, cardiogenesis, and neurogenesis.
authors.affiliation: Center for Transgene Technology and Gene Therapy, University of Leuven, Gasthuisberg O&N1, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Femke
authors.initials: F
authors.lastname: Zwerts
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
authors.forename: Astrid
authors.initials: A
authors.lastname: De Vriese
authors.forename: Saskia
authors.initials: S
authors.lastname: Pollefeyt
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Altura
authors.forename: Yuying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Peter
authors.initials: P
authors.lastname: Hill
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Oh
authors.forename: Claus
authors.initials: C
authors.lastname: Rieker
authors.forename: Désiré
authors.initials: D
authors.lastname: Collen
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
mesh_terms: D000818:Animals; D017209:Apoptosis; D003433:Crosses, Genetic; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005838:Genotype; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D009432:Neural Crest / Q000166:cytology*; D009436:Neural Tube Defects / Q000235:genetics*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D012097:Repressor Proteins; D000077022:Survivin
chemical_list: C117749:Birc5 protein, mouse; D017077:Culture Media, Conditioned; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012097:Repressor Proteins; D000077022:Survivin