Figure 5.

Interlinked signaling feedback loops control initiation, propagation, and termination of E–M feedback signaling. The SHH/GREM1/FGF E–M feedback loop is required for maintaining and propagating SHH signaling by the ZPA and up-regulation of FGF signaling in the AER. In mouse limb buds lacking Grem1, establishment of this E–M feedback signaling loop, distal progression of limb-bud development, and specification of digit identities is disrupted. The BMP antagonist GREM1 defines a regulatory node in this at least in parts self-regulatory limb signaling system as its transcription is positively regulated by BMPs (predominant during initiation) and SHH (predominant during progression), and inhibited by high FGF levels (predominant during termination of E–M feedback signaling).