Mice exclusively expressing the short isoform of Smad2 develop normally and are viable and fertile
Mice exclusively expressing the short isoform of Smad2 develop normally and are viable and fertile
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DOI：
10.1101/gad.1243205
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发表时间：
2005-01-01
影响因子：
10.5
通讯作者：
Robertson, EJ
中科院分区：
文献类型：
--
作者：
Dunn, NR;Koonce, CH;Robertson, EJ
Smad 2和Smad 3是TGF β/Nodal/激活素相关信号传导的密切相关效应子。Smad 3突变小鼠发育正常，而Smad 2在胚胎轴的模式化和定形内胚层的特化中起着重要作用。Smad 2外显子3的选择性剪接产生两种不同的蛋白质同种型。短Smad 2（Deltaexon 3）亚型，不像全长Smad 2，Smad 2（FL），保留DNA结合活性。在这里，我们表明，Smad 2（FL）和Smad 2（Deltaexon 3）在整个小鼠发育过程中共表达。Smad 2（Deltaexon 3）或Smad 3的定向表达，而不是Smad 2（FL），恢复了Smad 2缺陷型胚胎干（ES）细胞将后代贡献到野生型宿主胚胎中的定形内胚层的能力。经工程改造以专门表达Smad 2（Deltaexon 3）的小鼠正确地指定前后轴和定形内胚层，并且是存活的和可生育的。此外，将人Smad 3 cDNA引入小鼠Smad 2基因座中类似地挽救了前后图案化和定形内胚层形成，并导致成体存活力。总的来说，这些结果表明，短Smad 2（Deltaexon 3）同种型或Smad 3，但不是全长Smad 2，激活TGF β相关配体下游的所有必需靶基因，包括Nodal调控的那些。
Smad2 and Smad3 are closely related effectors of TGFbeta/Nodal/Activin-related signaling. Smad3 mutant mice develop normally, whereas Smad2 plays an essential role in patterning the embryonic axis and specification of definitive endoderm. Alternative splicing of Smad2 exon 3 gives rise to two distinct protein isoforms. The short Smad2(Deltaexon3) isoform, unlike full-length Smad2, Smad2(FL), retains DNA-binding activity. Here, we show that Smad2(FL) and Smad2(Deltaexon3) are coexpressed throughout mouse development. Directed expression of either Smad2(Deltaexon3) or Smad3, but not Smad2(FL), restores the ability of Smad2-deficient embryonic stem (ES) cells to contribute descendants to the definitive endoderm in wild-type host embryos. Mice engineered to exclusively express Smad2(Deltaexon3) correctly specify the anterior-posterior axis and definitive endoderm, and are viable and fertile. Moreover, introducing a human Smad3 cDNA into the mouse Smad2 locus similarly rescues anterior-posterior patterning and definitive endoderm formation and results in adult viability. Collectively, these results demonstrate that the short Smad2(Deltaexon3) isoform or Smad3, but not full-length Smad2, activates all essential target genes downstream of TGFbeta-related ligands, including those regulated by Nodal.