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Thromb Haemost. 1995 Jul;74(1):52-7.

The absence of the blood clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system.

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Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.


We have targeted the murine thrombomodulin (TM) gene in embryonic stem cells and generated embryos as well as mice with TM deficiency. The heterozygous TM-deficient (TM+/-) mice as compared to wild-type (TM+/+) littermates exhibit 50% reductions in the levels of TM mRNA and TM protein. However, TM+/- mice appear normal and are free of thrombotic complications. The homozygous TM-deficient (TM-/-) embryos die before E9.5. An overall retardation in growth and development of TM-/- embryos is first evident on E8.5 (8-12 somite pairs). However, no specific pathologic abnormalities are observed. These initial changes take place at a time when TM is normally expressed in the endoderm of the parietal yolk sac. The removal of E7.5 TM-/- embryos from maternal decidua and their subsequent culture in vitro allows development to proceed to stages not observed in vivo (13-20 somite) with the appearance of normal blood vessels in the visceral yolk sac and embryo. The results of our studies suggest that the failure of TM-/- embryos to survive at mid-gestation is a consequence of dysfunctional maternal-embryonic interactions caused by the absence of TM in the parietal yolk sac and demonstrate that the receptor is necessary for normal embryonic development in utero.

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