The Hedgehog pathway in its resting state

The Hedgehog gene encodes a secreted protein that is a ligand to the 12-transmembrane domain receptor known as Patched (PTCH).^13,14 In the absence of Hedgehog ligand, PTCH is located at the cell membrane and, in particular, in the primary cilium, a cellular structure present on most mammalian cells.¹ PTCH suppresses the activation of Smoothened (SMO), a 7-transmembrane protein, apparently by maintaining it in intracellular vesicles and preventing it from accessing the primary cilium.^1,15 In the absence of Hedgehog signal, Gli3 is processed into a transcriptional repressor and prevents activation of Hedgehog target genes.^16,17