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 Blood, 1 June 2007, Vol. 109, No. 11, pp. 4742-4752.
Prepublished online as a Blood First Edition Paper on February 13, 2007; DOI 10.1182/blood-2006-06-028068.

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Submitted June 8, 2006
Accepted February 7, 2007

Lack of endothelial cell survivin causes embryonic defects in angiogenesis, cardiogenesis, and neural tube closure

Femke Zwerts, Florea Lupu, Astrid De Vriese, Saskia Pollefeyt, Lieve Moons, Rachel Altura, Yuying Jiang, Patrick H Maxwell, Peter Hill, Hideyasu Oh, Claus Rieker, Desire Collen, Simon J Conway, and Edward M Conway*

Center for Transgene Technology and Gene Therapy, University of Leuven (KULeuven), Flanders Institute for Biotechnology (VIB), Belgium
Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
Children's Research Institute, Columbus, OH, United States
Faculty of Medicine, Imperial College, London, United Kingdom
German Cancer Research Center, Heidelberg, Germany
Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States

* Corresponding author; email: ed.conway{at}med.kuleuven.ac.be.

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 survivinlox/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 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. Additionally, 30% of mutant embryos had neural tube closure defects (NTD) 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.


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