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RESEARCH PAPER
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA
Smad2 and Smad3 are closely related effectors of TGF
/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(
exon3) isoform, unlike full-length Smad2, Smad2(FL), retains DNA-binding activity. Here, we show that Smad2(FL) and Smad2(exon3) are coexpressed throughout mouse development. Directed expression of either Smad2(exon3) 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(exon3) 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(exon3) isoform or Smad3, but not full-length Smad2, activates all essential target genes downstream of TGF-related ligands, including those regulated by Nodal.
[Keywords: Smad2; Smad3; alternative splicing; chimeras; definitive endoderm; redundancy]
Received July 22, 2004; revised version accepted November 2, 2004.
1 Present address: ES Cell International, 11 Biopolis Way, #05-06 Helios, Singapore 138667
2 Present address: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
EMAIL: Elizabeth.Robertson{at}well.ox.ac.uk; FAX 44-1865-287776.
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