The evolutionary origin of hedgehog proteins

Animal development is orchestrated largely by diffusible ligands of the Wnt, TGF-β, hedgehog (Hh) and FGF signaling pathways, as well as cell-surface molecules, such as Notch, cadherins, integrins and the immunoglobulin-like proteins [1,2]. Here, we show that Hh proteins are likely to have evolved very early in metazoan evolution by domain shuffling. We identify in sponges and cnidarians a transmembrane protein, Hedgling, that contains the amino-terminal, signalling domain of Hh (hedge-domain), as well as cadherin, EGF and immunoglobulin domains. While Hedgling appears to have been lost in bilaterians, the likely capture of a hedge-domain by the more ancient, intein derived hog-domain may have given rise to the Hh proteins.