Negative control of Smad activity by ectodermin/Tif1gamma patterns the mammalian embryo.
The definition of embryonic potency and induction of specific cell fates are intimately linked to the tight control over TGFbeta 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 Tif1gamma) 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/Tif1gamma is a crucial element in the cellular response to TGFbeta signals in mammalian tissues.
Morsut
Leonardo
L
Department of Medical Biotechnologies, Section of Histology and Embryology, University of Padua, viale Colombo 3, 35126 Padua, Italy.
Yan
Kai-Ping
KP
Enzo
Elena
E
Aragona
Mariaceleste
M
Soligo
Sandra M
SM
Wendling
Olivia
O
Mark
Manuel
M
Khetchoumian
Konstantin
K
Bressan
Giorgio
G
Chambon
Pierre
P
Dupont
Sirio
S
Losson
Régine
R
Piccolo
Stefano
S
D000483:Alleles; D000818:Animals; D019521:Body Patterning; D002454:Cell Differentiation; D003433:Crosses, Genetic; D004475:Ectoderm / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010641:Phenotype; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D051785:Smad Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C491420:Trim33 protein, mouse