Deconstructing the hedgehog pathway in development and disease

Abstract

The Hedgehog (Hh) family of secreted signaling proteins is a master regulator of cell fate determination in metazoans, contributing to both pattern formation during embryonic development and postembryonic tissue homeostasis. In a universally used mode of action, graded distribution of Hh protein induces differential cell fate in a dose-dependent manner in cells that receive Hh. Though much of this pathway has been elucidated from genetically based studies in model organisms, such as Drosophila and mice, the importance of Hh-mediated signaling in humans is clearly evident from malformations and a broad range of cancers that arise when the pathway is corrupted.

Fig. 1

Hh signaling in animals. (A) Hh production is highly conserved between Drosophila and mammals (middle). Autocatalytic cleavage of the Hh precursor protein yields a cholesterol-modified signaling peptide (HhN), which is further palmitoylated by Skinny Hedgehog (Ski), then released from the cell by Disp (Drosophila) or Disp1 (mammals). In Drosophila (left), the released lipophilic HhN is incorporated into lipophorin complexes (not shown) and distributed to other cells with the help of heparan sulfate proteoglycans (Dally and Dlp; also not shown). The suppressive action of Ptc or Ptch1 on Smo is conserved in Hh-responsive cells from Drosophila (left) and mammals (right). Members of the CDO receptor family (not shown), including Ihog, facilitate Hh binding and inhibition of Ptc or Ptch1, allowing activation of Smo. In Drosophila, Dlp also appears to facilitate Hh response. Smo-mediated regulation of Ci (Drosophila) or Gli (mammals) nuclear localization and proteolytic processing into a repressor (CiR or Gli3R) depends on Cos2, Fu, and Su(fu) in Drosophila, and proteins that function in the primary cilium in mammals. The mechanism by which Smo inhibits the pathway suppressor Su(fu) in mammals is unknown. (B) Tumors with aberrant Hh pathway activity in Gorlin’s syndrome, as well as their sporadic counterparts, frequently harbor mutations in Ptch1. Other tumors for which molecular lesions have not been defined also exhibit aberrant Hh pathway response. References for most of the tumors described here can be found in (16).