Combinatorial activities of Smad2 and Smad3 regulate mesoderm formation and patterning in the mouse embryo
Combinatorial activities of Smad2 and Smad3 regulate mesoderm formation and patterning in the mouse embryo
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DOI：
10.1242/dev.01072
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发表时间：
2004-04-01
期刊：
影响因子：
4.6
通讯作者：
Bikoff, EK
中科院分区：
文献类型：
--
作者：
Dunn, NR;Vincent, SD;Bikoff, EK
转化生长因子β/激活素/节点（Nodal）受体可激活细胞内效应蛋白Smad2和Smad3。这些密切相关分子的功能活性已在细胞系中得到广泛研究。我们发现，从囊胚期开始，这两种蛋白均在小鼠早期胚胎中表达，并在体外介导依赖Foxh1的节点（Nodal）自调节增强子的激活。对它们表达比例的基因操作表明，Smad3在植入后的早期阶段提供关键信号。因此，在存在一个野生型Smad2拷贝的情况下，Smad3缺失会导致前轴中内胚层产生受损，而从外胚层选择性去除Smad2和Smad3还会破坏轴旁和近轴中胚层衍生物的特化。最后，我们证明Smad2和Smad3双纯合突变体完全缺乏中胚层且无法进行原肠胚形成。总之，这些结果表明，剂量依赖性的Smad2和Smad3信号协同介导小鼠早期胚胎中的细胞命运决定。
TGFbeta/activin/Nodal receptors activate both Smad2 and Smad3 intracellular effector proteins. The functional activities of these closely related molecules have been extensively studied in cell lines. We show both are expressed in the early mouse embryo from the blastocyst stage onwards and mediate Foxh1-dependent activation of the Nodal autoregulatory enhancer in vitro. Genetic manipulation of their expression ratios reveals that Smad3 contributes essential signals at early post-implantation stages. Thus, loss of Smad3 in the context of one wild-type copy of Smad2 results in impaired production of anterior axial mesendoderm, while selective removal of both Smad2 and Smad3 from the epiblast additionally disrupts specification of axial and paraxial mesodermal derivatives. Finally, we demonstrate that Smad2;Smad3 double homozygous mutants entirely lack mesoderm and fail to gastrulate. Collectively, these results demonstrate that dose-dependent Smad2 and Smad3 signals cooperatively mediate cell fate decisions in the early mouse embryo.