Frontiers in hedgehog signal transduction.

The hedgehog (Hh) pathway is a paracrine cell–cell communicaion system discovered in Drosophila over thirty years ago and then tudied for its central role in development in both vertebrates and nvertebrates. Hh was later implicated in other processes, includng adult stem cell maintenance, cell migration, axon guidance and ancer, in a wide range of organisms. Its identification as an oncoenic driver in human medulloblastoma and basal cell carcinoma ltimately lead to a class of anti-Hh drugs that have entered clinial use. The arc of the Hh story, from genetic studies of Drosophila egmentation to a cancer drug, is often cited, rightfully, as an inspiational example of the power of basic research. While the core omponents of this pathway, conserved across evolution, have been nown for years, the cell biological and biochemical mechanisms hat drive ligand dissemination and signal propagation continue to resent unsolved mysteries. The six articles in this issue of Semiars in Cell and Developmental Biology highlight the frontiers in both he biology and mechanism of Hh research and illustrate how studes of this pathway continue to uncover novel principles in signal ransduction. Hh ligands are hydrophobic, dually lipidated molecules whose nique biogenesis involves an autoproteolytic reaction that leaves cholesterol molecule covalently attached to the C-terminal end. he mechanism by which this greasy ligand is secreted and disersed through surrounding tissues remains an active area of nvestigation, with general implications for understanding how evelopmental signals influence cell fates at a distance. Kornerg and Guerrero discuss new insights into how Hh ligands re secreted and presented to target cells, including the role of ytonemes, actin-based filopodia-like extensions, in the transport f Hh ligands (and other secreted signals) between source and taret cells. They discuss the idea that Hh signaling occurs by cell–cell ontact mediated by cytonemes, similar to synaptic transmision between neurons. They term these contacts morphogenetic ynapses. Once Hh ligands are received at target cells by a receptor comlex whose central component is the 12-pass transmembrane (TM) rotein Patched (Ptc), the task of signal transmission across the embrane is carried out by Smoothened (Smo), a 7-pass TM proein that is a member of the G-protein coupled receptor (GPCR) uperfamily. Smo is the target for all currently used Hh drugs, but emarkably, the mechanism by which Ptc regulates Smo and Smo, in urn, activates downstream signaling remains enigmatic. One of the ew discoveries over the past decade was that Hh signaling in verterates depends on the primary cilium, a solitary microtubule-based