Figure 7.
Model of an ALK2/ALK3-dependent balance of SMAD1/5 or p38 signaling in stalk and tip cell specification. Our data suggest that an ALK2-dependent activation of SMAD1/5 signaling results in expression of the stalk cell-associated genes ID1, ID2, HES1 and FLT1, while the tip cell–associated genes DLL4 and KDR are repressed. On the other hand, ALK3 is required for efficient sprouting and distinct receptor complexes activate p38 signaling. This results in expression of the tip cell–associated genes DLL4 and KDR, as well as HSP27-dependent collective migration. Distinct BMP receptor complexes exist as preformed complexes (PFCs) or as BMP ligand-induced signaling complexes (BISCs) that activate SMAD1/5 or p38 signaling respectively. This allows a cell-autonomous balance of SMAD and non-SMAD signaling depending on expression levels and complex formation of BMP receptors.