Figure 1.

Key features of the Shh pathway. (a) Simplified schematic of the ‘canonical’ Shh pathway. Shh binds to the membrane-bound receptor Patched1, relieving Patched1's constitutive inhibition of Smoothened (Smo). Upon Shh signalling, Smo is thus able to interact with Gli transcription factors, which initiate transcription of Shh target genes such as the gene encoding Patched1. This gives rise to ligand-dependent antagonism (LDA; red dotted flathead arrow), whereby Shh network activity stimulates the expression of its own repressor (Ptc). Red flathead arrows indicate effects that occur in the presence of Shh binding. (b) Simplified schematic of neural tube patterning by Shh. Shh is expressed by the notochord (NC), and movement of Shh into the floor plate (FP) induces Shh expression in the FP. From here, Shh forms a concentration gradient from ventral to dorsal in the developing neural tube, specifying neural progenitors (p0–3, pMN). Dotted lines indicates progenitor region. (c) Simplified schematic of limb bud digit patterning by Shh. Shh is secreted from the zone of polarizing activity (ZPA) and travels through the posterior limb bud, specifying posterior identity through Gli1 and Gli3 induction. (d) Experimental evidence for Patched1-dependent ligand-dependent antagonism on developing hair follicles, adapted from [29]. (i) The levels of Gli1 activity resulting from a proximo-distal Shh concentration gradient. (ii) In a Patched1 genetic knockout, the Hedgehog gradient is no longer attenuated via ligand-dependent antagonism, so high concentration-dependent cell identities are found more distally. Red dotted line is the shape of the wild-type Shh gradient.