The Sonic Hedgehog Signaling Pathway

Abstract The highly conserved hedgehog (Hh) family of signaling proteins triggers crucial processes in early vertebrate and invertebrate development, including cell fate speci7cation, patterning, and organogenesis. The development of a large number of organ systems is directly affected by the Hh signaling pathway. Indeed, the Hh ligands, patched and smoothened transmembrane proteins, and the Ci/Gli family of transcription factors are at the nexus of mesodermal development and they are critical to epithelial–mesenchymal interactions throughout the body. It is also becoming clear that a relatively small number of pathways, the Hh pathway included, operating in a combinatorial manner are responsible for pattern formation in early development. Genetic and epigenetic aberrations, pharmacological perturbations, and environmental insults that impact the Hh signaling pathway translate to various developmental disorders and diseases, including cancer (reviewed in Villavicencio et al., 2000; Cohen, 2003). The wide variety of diseases associated with the genes in this pathway usually involves the organs and tissues in which the pathway normally operates, including the brain, gastrointestinal tract, skin, prostate, ovary, lung, muscle, and bone. Although still incompletse, our understanding of the Hh pathway has progressed rapidly in the past few years, promising a future of accurate diagnosis and effective treatment of diseases related to defects in Hh signaling. Several proteins cooperatively transduce an extracellular signal from the Hh ligand through a cascade of steps, the net result of which is a change in the pattern of expression of genes within the target cell. This change then coordinates and regulates proliferation and differentiation of various cells in a way that develops and maintains pattern. The main cast of characters in the story includes Drosophila Hh and the vertebrate homologs, Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh); Drosophila Patched (Ptc) and the vertebrate homologs Ptc1 and Ptc2; Drosophila and vertebrate Smoothened (Smo); Drosophila Costal 2 (Cos2), vertebrate Kif family members, and yet unidenti7ed vertebrate homolog(s); Drosophila and vertebrate Fused (Fu); Drosophila and vertebrate Suppressor of fused [Su(fu)]; Drosophila Cubitus interruptus (Ci) and the vertebrate homologs, Gli1, Gli2, and Gli3; and a variety of interacting proteins and intracellular regulators. In this chapter, we will examine the components and function of the pathway in the Drosophila (fruit My) model system from where most of the seminal discoveries originate and in vertebrate systems, including mouse and human, which exhibit unique features.