Endoglin, an ancillary TGFβ receptor, is required for extraembryonic angiogenesis and plays a key role in heart development
Endoglin, an ancillary TGFβ receptor, is required for extraembryonic angiogenesis and plays a key role in heart development
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DOI：
10.1006/dbio.1999.9534
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发表时间：
2000-01-01
影响因子：
2.7
通讯作者：
Diamond, AG
中科院分区：
文献类型：
--
作者：
Arthur, HM;Ure, J;Diamond, AG
内皮糖蛋白 (CD105) 在哺乳动物的内皮细胞和造血细胞表面表达，并与 TGF β 亚型 1 和 3 以及 I 型和 II 型 TGF β 受体的信号复合物结合。内皮糖蛋白表达在血管生成、伤口愈合和炎症过程中增加，所有这些都与 TGF β 信号传导和血管结构的改变有关。内皮糖蛋白基因突变与遗传性疾病 1 型遗传性出血性毛细血管扩张症 (HHT1) 的关联进一步表明了内皮糖蛋白对正常血管结构的重要性，该病是一种以血管畸形出血为特征的疾病。为了更详细地研究内皮糖蛋白在体内的作用并致力于开发 HHT1 动物模型，我们衍生了携带内皮糖蛋白基因有针对性的无义突变的小鼠。对这些小鼠的研究表明，内皮糖蛋白对于早期发育至关重要。内皮糖蛋白突变的纯合胚胎在交配后 10.5 天后无法发育，并且无法在卵黄囊中形成成熟的血管。这种表型与 TGF β 1 和 TGF β 受体 II 敲除小鼠的表型非常相似，表明在胚胎外血管发育过程中，体内需要内皮糖蛋白来实现 TGF β 1 信号传导。此外，我们在纯合内皮糖蛋白缺陷胚胎中观察到心脏缺陷，表明内皮糖蛋白也在心脏发生中发挥作用。我们预计杂合小鼠最终将成为 HHT1 的有用疾病模型，因为一些个体的血管扩张且脆弱，类似于 HHT 患者中所见的血管畸形，(C) 2000 学术出版社。
Endoglin (CD105) is expressed on the surface of endothelial and haematopoietic cells in mammals and binds TGF beta isoforms 1 and 3 in combination with the signaling complex of TGF beta receptors types I and II. Endoglin expression increases during angiogenesis, wound healing, and inflammation, all of which are associated with TGF beta signaling and alterations in vascular structure. The importance of endoglin for normal vascular architecture is further indicated by the association of mutations in the endoglin gene with the inherited disorder Hereditary Haemorrhagic Telangiectasia Type 1 (HHT1), a disease characterised by bleeding from vascular malformations. In order to study the role of endoglin in vivo in more detail and to work toward developing an animal model of HHT1, we have derived mice that carry a targeted nonsense mutation in the endoglin gene. Studies on these mice have revealed that endoglin is essential for early development. Embryos homozygous for the endoglin mutation fail to progress beyond 10.5 days postcoitum and fail to form mature blood vessels in the yolk sac. This phenotype is remarkably similar to that of the TGF beta 1 and the TGF beta receptor II knockout mice, indicating that endoglin is needed in vivo for TGF beta 1 signaling during extraembryonic vascular development. In addition, we have observed cardiac defects in homozygous endoglin-deficient embryos, suggesting endoglin also plays a role in cardiogenesis. We anticipate that heterozygous mice will ultimately serve as a useful disease model for HHT1, as some individuals have dilated and fragile blood vessels similar to vascular malformations seen in HHT patients, (C) 2000 Academic Press.