Patched-Smoothened, Gli transcription factors, and gradient interpretation
The Hedgehog (Hh) pathway transduces extracellular Sonic Hedgehog morphogen into graded transcriptional responses via Gli zinc-finger transcription factors. In the OFF state, Patched1 (PTCH1) tonically inhibits Smoothened (SMO), allowing PKA/GSK3/CK1 to phosphorylate Gli2/3, triggering partial proteolysis into transcriptional repressors (GliR) that silence Hh target genes. SHH binding to PTCH1 relieves SMO inhibition; active SMO accumulates in the primary cilium, recruits Suppressor of Fused (SUFU), and redirects Gli2/3 toward full-length activator forms (GliA) that activate Ptch1, Gli1, and Hhip (feedback targets). The gradient is read as three zones: GliR-dominant (low SHH → V3/MN progenitors in neural tube), intermediate, and GliA-dominant (high SHH → floor plate). PTCH1 heterozygous loss-of-function causes Gorlin syndrome (basal cell carcinoma predisposition).