The absence of the blood clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system.
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.
Rosenberg
R D
RD
Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.
D000818:Animals; D001483:Base Sequence; D002319:Cardiovascular System / Q000196:embryology*; D002678:Chimera; D005314:Embryonic and Fetal Development / Q000235:genetics; D004707:Endoderm / Q000473:pathology; D005260:Female; D005313:Fetal Death / Q000196:embryology / Q000235:genetics*; D005317:Fetal Growth Retardation / Q000235:genetics / Q000473:pathology; D017353:Gene Deletion; D005804:Genes, Lethal; D005865:Gestational Age; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011247:Pregnancy; D011995:Recombination, Genetic; D013234:Stem Cells; D018180:Thrombomodulin / Q000172:deficiency* / Q000235:genetics; D015017:Yolk Sac / Q000098:blood supply / Q000473:pathology
D018180:Thrombomodulin