Shh gradients along the ventral–dorsal axis of the neural tube direct neuronal differentiation via two transmembrane proteins: Patched (Ptc) and Smoothened (Smo). Removal of Shh during development is known to cause massive apoptosis in the neural tube, but this outcome was thought to be a byproduct of the failure of cells to differentiate. Mehlen's group now shows, however, that death is actively switched on by unbound Ptc.
Ptc expression in cultured cells induced apoptosis unless Shh was added. Similar results were seen with overexpression of Ptc in the neural tube. “Wherever Patched is expressed, those cells becomes dependent on the presence of the ligand,” says Mehlen. This action probably shapes the neural chord by removing cells that fall outside the reach of Shh.
Ptc seems to be activated for apoptosis by caspase cleavage of its COOH-terminal tail, with Shh somehow preventing this cleavage, perhaps via downstream effectors of Smo. A caspase-cleaved version of Ptc initiates apoptosis even in the presence of Shh.
The ligandless action of Ptc is similar to that of UNC5H and DCC, which were dubbed dependence receptors because they induce cell death in vitro unless their ligands are present. The ability to induce apoptosis may make all three putative tumor suppressors “because they control proliferation of cells that are out of their normal context,” says Mehlen. ▪