Mice exclusively expressing the short isoform of Smad2 develop normally and are viable and fertile

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Abstract
Smad2 and Smad3 are closely related effectors of TGFβ/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(Δexon3) isoform, unlike full-length Smad2, Smad2(FL), retains DNA-binding activity. Here, we show that Smad2(FL) and Smad2(Δexon3) are coexpressed throughout mouse development. Directed expression of either Smad2(Δexon3) 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(Δexon3) 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(Δexon3) isoform or Smad3, but not full-length Smad2, activates all essential target genes downstream of TGFβ-related ligands, including those regulated by Nodal.