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 embryonic day 9.5. An overall retardation in growth and development of TM-/- embryos is first evident on embryonic day 8.5 (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 parietal yolk sac. The removal of embryonic day 7.5 TM-/- embryos from maternal decidua and their subsequent culture in vitro allow development to proceed to stages not observed in vivo (13-20 somite pairs) 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.
Healy
A M
AM
Department of Biology, Massachusetts Institute of Technology, Cambridge 02139.
Rayburn
H B
HB
Rosenberg
R D
RD
Weiler
H
H
D000818:Animals; D001483:Base Sequence; D002319:Cardiovascular System / Q000196:embryology*; D002678:Chimera; D003433:Crosses, Genetic; D005314:Embryonic and Fetal Development; D005260:Female; D018390:Gene Targeting; D005804:Genes, Lethal / Q000502:physiology*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D012333:RNA, Messenger / Q000096:biosynthesis; D013234:Stem Cells; D018180:Thrombomodulin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D012333:RNA, Messenger; D018180:Thrombomodulin