Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds

The secreted bone-morphogenetic-protein (BMP) antagonist Gremlin, is shown to relay the sonic hedgehog (SHH) signal from the polarizing area to the apical ectodermal ridge (AER). Mesenchymal Gremlin expression is lost in limb buds of mouse embryos homozygous for the limb deformity mutation. If Gremlin-expressing cells are grafted into ld mutant limb buds, Fgf4 expression is rescued and the SHH/FGF4 feedback loop is restored.