Fig. 7. Dose-dependent Smad2 and Smad3 signals pattern the primitive streak. Columns are grouped according to genotypes derived from intercrossing Smad2;Smad3 double heterozygous mice (left) and specific elimination of Smad2 in the epiblast in the context of progressive loss of Smad3 (right). The identical phenotypes of Smad2^+/–;Smad3^–/– and Sox2Cre;Smad2^CA/Robm1 mutant embryos (columns with black perimeter) suggest that Smad2 is the predominant intracellular effector of Nodal signaling during patterning of the primitive streak. This observation establishes the hypothetical dose relationship whereby one Smad3 wild-type allele (red) is 50% less active than a Smad2 wild-type allele (blue). Accordingly, the combined Smad2/3 dosage is then calculated for each genotype analyzed in our studies. Three phenotypic thresholds emerge below which patterning of the primitive streak is sequentially compromised. The first eliminates the anterior AME followed by the node, remaining axial mesoderm (notochord) and definitive endoderm, and finally the lateral and paraxial mesoderm.