The TGFβ activated kinase TAK1 regulates vascular development in vivo
The TGFβ activated kinase TAK1 regulates vascular development in vivo
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DOI：
10.1242/dev.02333
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发表时间：
2006-04-15
期刊：
影响因子：
4.6
通讯作者：
Coucouvanis, E
中科院分区：
文献类型：
--
作者：
Jadrich, JL;O'Connor, MB;Coucouvanis, E
TGF β激活激酶1（TAK1）是一种MAPKKK，在细胞培养系统中已显示在多种信号分子（包括TGF β）的下游起作用。然而，它在脊椎动物发育过程中的作用还没有被真正的功能丧失研究所研究。在这份报告中，我们描述的表型小鼠胚胎中的Tak1基因已被灭活的基因陷阱插入。Tak1突变体胚胎在胚胎固有和卵黄囊的发育血管中表现出缺陷。这些缺陷包括血管扩张和分支错误，以及缺乏血管平滑肌。Tak1突变胚胎的表型与TGF β I型受体Alk1和III型受体内皮糖蛋白的功能丧失突变所表现出的表型惊人地相似，这表明TAK1可能是血管发育过程中TGF β信号的主要效应子。与这个观点相一致的是，我们在斑马身上发现。sh、吗啉代与TAK1和ALK 1协同作用以增强Alk 1血管表型。此外，我们表明，TAK1的过表达能够挽救由吗啉敲低ALK 1产生的血管缺损。总之，这些结果表明，TAK1可能是调节脊椎动物血管发育的TGF β信号转导通路的重要下游组分。此外，由于内皮糖蛋白和ALK 1突变的杂合性分别导致称为遗传性出血性毛细血管扩张症1和2的人类综合征，我们的研究结果提出了人类TAK 1突变可能导致这种疾病的可能性。
TGF beta activated kinase 1 (TAK1) is a MAPKKK that in cell culture systems has been shown to act downstream of a variety of signaling molecules, including TGF beta. Its role during vertebrate development, however, has not been examined by true loss-of-function studies. In this report, we describe the phenotype of mouse embryos in which the Tak1 gene has been inactivated by a genetrap insertion. Tak1 mutant embryos exhibit defects in the developing vasculature of the embryo proper and yolk sac. These defects include dilation and misbranching of vessels, as well as an absence of vascular smooth muscle. The phenotype of Tak1 mutant embryos is strikingly similar to that exhibited by loss-of-function mutations in the TGF beta type I receptor Alk1 and the type III receptor endoglin, suggesting that TAK1 may be a major effector of TGF beta signals during vascular development. Consistent with this view, we find that in zebra. sh, morpholinos to TAK1 and ALK1 synergize to enhance the Alk1 vascular phenotype. Moreover, we show that overexpression of TAK1 is able to rescue the vascular defect produced by morpholino knockdown of ALK1. Taken together, these results suggest that TAK1 is probably an important downstream component of the TGF beta signal transduction pathway that regulates vertebrate vascular development. In addition, as heterozygosity for mutations in endoglin and ALK1 lead to the human syndromes known as hereditary hemorrhagic telangiectasia 1 and 2, respectively, our results raise the possibility that mutations in human TAK1 might contribute to this disease.