Lack of endothelial cell survivin causes embryonic defects in angiogenesis, cardiogenesis, and neural tube closure.
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.
Zwerts
Femke
F
Center for Transgene Technology and Gene Therapy, University of Leuven, Gasthuisberg O&N1, Herestraat 49, 3000 Leuven, Belgium.
Lupu
Florea
F
De Vriese
Astrid
A
Pollefeyt
Saskia
S
Moons
Lieve
L
Altura
Rachel A
RA
Jiang
Yuying
Y
Maxwell
Patrick H
PH
Hill
Peter
P
Oh
Hideyasu
H
Rieker
Claus
C
Collen
Désiré
D
Conway
Simon J
SJ
Conway
Edward M
EM
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
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