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E. C. Bailey et al.
baram et al. 1996; Wicking et al. 1997). This model would predict that
inhibitors of Shh block signal transduction by keeping Ptc in an active
state regardless of the presence of Shh. How this might happen mechanistically and whether the drugs would interact directly with Ptc are
unresolved questions. Reception of the Hh signal may involve endocytosis of Hh, Ptc, and Smo and subsequent intracellular movement. This
would be consistent with Ptc localization in Drosophila where the
protein is found at the plasma membrane and in intracellular vesicles
(Capdevila et al. 1994). Interestingly, the sterol sensor proteins HMO
CoA reductase and SCAP are not found at the cell surface but instead
localize to the endoplasmic reticulum. Whether Ptc is a target of the
cholesterol inhibitors or not, it is clear that sterols have an important role
in Hh signaling. Functional studies of the conserved regions between
Ptc and NPC I, including the putative sterol sensor, should increase our
understanding of how Ptc and other components regulate signaling to
control development and proliferation.
12.6 Conclusions
hh was originally identified in Drosophila as a gene involved in early
embryonic patterning (Nusslein-Volhard and Wieschaus 1980). Since its
discovery, a number of pathway components have been found in a wide
range of animals. As in flies, hh family members in vertebrates are
crucial to the proper development of a number of tissues and organ
systems. Recent work has implicated Hh signaling components in human diseases and tumorigenesis. Mutations in the ligand, Shh, the
reception complex, Ptc and Smo, and the transcription factors, Olil and
Oli3, have all been implicated as primary causes of human diseases.
Furthermore, a growing body of evidence continues to extend the roles
of sterols in Hh signaling, from Hh biosynthesis to the response of target
tissues to Hh. The homology of Ptc to NPC I and to proteins regulated
by sterols has provided exciting possibilities on how Hh signaling might
be controlled. Future studies on Hh signal reception, how signaling is
relayed from membrane to cytoplasm, and how sterols modulate these
events, will greatly enhance our understanding of Hh signaling. This
pathway has provided, and will continue to provide, valuable insights
into the basic processes of development and disease.
E. C. Bailey et al.
baram et al. 1996; Wicking et al. 1997). This model would predict that
inhibitors of Shh block signal transduction by keeping Ptc in an active
state regardless of the presence of Shh. How this might happen mechanistically and whether the drugs would interact directly with Ptc are
unresolved questions. Reception of the Hh signal may involve endocytosis of Hh, Ptc, and Smo and subsequent intracellular movement. This
would be consistent with Ptc localization in Drosophila where the
protein is found at the plasma membrane and in intracellular vesicles
(Capdevila et al. 1994). Interestingly, the sterol sensor proteins HMO
CoA reductase and SCAP are not found at the cell surface but instead
localize to the endoplasmic reticulum. Whether Ptc is a target of the
cholesterol inhibitors or not, it is clear that sterols have an important role
in Hh signaling. Functional studies of the conserved regions between
Ptc and NPC I, including the putative sterol sensor, should increase our
understanding of how Ptc and other components regulate signaling to
control development and proliferation.
12.6 Conclusions
hh was originally identified in Drosophila as a gene involved in early
embryonic patterning (Nusslein-Volhard and Wieschaus 1980). Since its
discovery, a number of pathway components have been found in a wide
range of animals. As in flies, hh family members in vertebrates are
crucial to the proper development of a number of tissues and organ
systems. Recent work has implicated Hh signaling components in human diseases and tumorigenesis. Mutations in the ligand, Shh, the
reception complex, Ptc and Smo, and the transcription factors, Olil and
Oli3, have all been implicated as primary causes of human diseases.
Furthermore, a growing body of evidence continues to extend the roles
of sterols in Hh signaling, from Hh biosynthesis to the response of target
tissues to Hh. The homology of Ptc to NPC I and to proteins regulated
by sterols has provided exciting possibilities on how Hh signaling might
be controlled. Future studies on Hh signal reception, how signaling is
relayed from membrane to cytoplasm, and how sterols modulate these
events, will greatly enhance our understanding of Hh signaling. This
pathway has provided, and will continue to provide, valuable insights
into the basic processes of development and disease.