ABSENCE OF THE BLOOD-CLOTTING REGULATOR THROMBOMODULIN CAUSES EMBRYONIC LETHALITY IN MICE BEFORE DEVELOPMENT OF A FUNCTIONAL CARDIOVASCULAR-SYSTEM
ABSENCE OF THE BLOOD-CLOTTING REGULATOR THROMBOMODULIN CAUSES EMBRYONIC LETHALITY IN MICE BEFORE DEVELOPMENT OF A FUNCTIONAL CARDIOVASCULAR-SYSTEM
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DOI：
10.1073/pnas.92.3.850
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发表时间：
1995-01-31
影响因子：
11.1
通讯作者：
WEILER, H
中科院分区：
文献类型：
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作者：
HEALY, AM;RAYBURN, HB;WEILER, H
我们已经在胚胎干细胞中定位了小鼠血栓调节蛋白(TM)基因，并产生了TM缺乏的胚胎和小鼠。与野生型(TM(+)/(+))小鼠相比，TM杂合缺陷(TM(+)/(-))小鼠的TM mRNA和TM蛋白水平降低了50%。然而，TM(+)/(-)小鼠看起来正常，没有血栓并发症。纯合子TM缺失(TM(-)/(-))胚胎在胚胎9.5天前死亡。TM(-)/(-)胚胎的生长发育在胚胎第8.5天(8-12个体节对)表现出明显的发育迟缓。然而，没有观察到特殊的病理异常。这些最初的变化发生在TM在顶卵黄囊中正常表达的时候。从母体蜕膜中取出7.5d的胚胎TM(-)/(-)胚胎并进行体外培养，可以使胚胎发育到体内观察不到的阶段(13-20个体节对)，内脏卵黄囊和胚胎中出现正常的血管。我们的研究结果表明，TM(-)/(-)胚胎在妊娠中期存活的失败是由于顶卵黄囊中缺乏TM而导致母体-胚胎相互作用功能障碍的结果，并表明该受体是子宫内正常胚胎发育所必需的。
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.