This requirement of Hh-signal activation at precise levels and in the right compartments is in agreement with a recent study demonstrating that β-catenin-induced de novo HF formation was not only dependent on stromal Hh signaling, but also required two intact Smo alleles (for a maximal Hh-pathway activation) to enable efficient de novo HF induction (Lichtenberger et al., 2016). The gene discussed is SMO; the disease is hydrops fetalis.