The definition of embryonic potency and induction of specific cell fates are intimately linked to the tight control over TGFβ signaling. Although extracellular regulation of ligand availability has received considerable attention in recent years, surprisingly little is known about the intracellular factors that negatively control Smad activity in mammalian tissues. By means of genetic ablation, we show that the Smad4 inhibitor ectodermin (Ecto, also known as Trim33 or Tif1γ) is required to limit Nodal responsiveness in vivo. New phenotypes, which are linked to excessive Nodal activity, emerge from such a modified landscape of Smad responsiveness in both embryonic and extra-embryonic territories. In extra-embryonic endoderm, Ecto is required to confine expression of Nodal antagonists to the anterior visceral endoderm. In trophoblast cells, Ecto precisely doses Nodal activity, balancing stem cell self-renewal and differentiation. Epiblast-specific Ecto deficiency shifts mesoderm fates towards node/organizer fates, revealing the requirement of Smad inhibition for the precise allocation of cells along the primitive streak. This study unveils that intracellular negative control of Smad function by ectodermin/Tif1γ is a crucial element in the cellular response to TGFβ signals in mammalian tissues.
The authors declare no competing financial interests.
Author contributions
L.M., S.D. and S.P. designed experiments and analyzed data. L.M. performed in situs and post in situ embryo genotyping; E.E. performed breedings, immunofluorescence staining and helped with in situs; M.A. performed real-time PCR and TS cell experiments with S.D., and colony genotyping with S.S.; K.Y., O.W., M.M., K.K., P.C. and R.L. designed and generated the Ecto knockout alleles; S.P. and S.D. wrote the paper.
Supplementary material
