Arkadia degrades SNON to activate level-specific NODAL responses

NODAL, a transforming-growth-factor-beta (TGF-β)-family ligand, exhibits morphogen functions during gastrulation via its activated transcriptional effectors, SMAD2/3. High signalling-levels specify cell-fates inducing anterior/head, lower specify posterior, and absence abolishes gastrulation. How cells assess NODAL-signalling levels to initiate specific gene expression patterns remains elusive. Here, we show that the co-repressor SNON represses a subset of NODAL-SMAD2/3 target-genes and that the activation of these genes depends on SNON removal by the E3-ubiquitin-ligase Arkadia (RNF111). As Arkadia degrades SNON in complex with SMAD2/3, high NODAL-SMAD2/3 signalling is required to saturate SNON and remove it allowing the activation of SNON-repressed targets. Arkadia-null embryos lack anterior/head and are rescued by removal of SNON, confirming that SNON represses anterior development which requires also high NODAL-signalling. Therefore, cells assess NODAL-signalling levels by pairing SMAD2/3 to SNON triggering their degradation by Arkadia. Only high signalling removes SNON that leads to derepression of the SNON-repressed SMAD2/3-targets achieving level specific responses.