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

Journal article

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.

Authors: Dunn, N; Koonce, C; Anderson, D; Islam, A; Bikoff, E

• Publication status: Published
• Journal: Genes and development
• Volume: 19
• Issue: 1
• Pages: 152-163
• Publication date: 2005-01-01
• DOI: 10.1101/gad.1243205
• EISSN: 1549-5477
• ISSN: 0890-9369
• Language: English
• Keywords: Humans; Animals; Embryo, Mammalian; Growth and Development; Stem Cells; Smad3 Protein; Trans-Activators; Mice, Mutant Strains; Gene Expression Regulation, Developmental; Mice; Endoderm; Protein Isoforms; Mice, Transgenic; Body Patterning; Fertility; DNA-Binding Proteins; Fetal Viability; Smad2 Protein