It should be pointed out that due to our failure to successfully apply anti-pSmad1/5/8 immuno-histochemistry in tissues from embryos earlier than stage E19.5, we cannot conclusively rule out for the moment activation of the canonical BMP pathway at the tips of the early branching endoderm. Further studies will be required to assess whether the BRE-eGFP reporter is not active in the distal endoderm because: a) non-canonical BMP pathways are primarily involved; b) the canonical BMP pathway is active however, does not reach the activation threshold required to activate the BRE-eGFP reporter; or c) that the dynamic balance between the mesenchyme and endoderm which keeps the BRE-eGFP reporter inactive most of the time (Figure 5 ), allows at critical points along the branching process transient spikes of canonical BMP pathway signaling to reach the nucleus and regulate expression of target genes.