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Keywords:

  • nevoid basal cell carcinoma syndrome;
  • holoprosencephaly;
  • Smith–Lemli–Opitz syndrome;
  • Greig cephalopolysyndactyly syndrome;
  • Pallister–Hall syndrome;
  • Carpenter syndrome;
  • Rubinstein–Taybi syndrome;
  • vertebrate hedgehog signaling;
  • cholesterol moiety;
  • palmitate;
  • role of cholesterol;
  • primary cilium;
  • intraflagellar transport;
  • enhancer elements;
  • cell surface and extracellular matrix proteins;
  • target genes;
  • intracellular transduction;
  • Cdo/Boc;
  • oxysterols;
  • Vitamin D3;
  • Hip1;
  • Gas1;
  • Wnt;
  • Smo;
  • NODAL;
  • BMP;
  • PTCH1;
  • PTCH2;
  • DISP1;
  • SHH;
  • ZIC2;
  • SIX3;
  • TGIF;
  • GLI2;
  • FOXH1;
  • TDGF1;
  • DHCR7;
  • GLI3;
  • RAB23;
  • CBP

Abstract

In vertebrate hedgehog signaling, hedgehog ligands are processed to become bilipidated and then multimerize, which allows them to leave the signaling cell via Dispatched 1 and become transported via glypicans and megalin to the responding cells. Hedgehog then interacts with a complex of Patched 1 and Cdo/Boc, which activates endocytic Smoothened to the cilium. Patched 1 regulates the activity of Smoothened (1) via Vitamin D3, which inhibits Smoothened in the absence of hedgehog ligand or (2) via oxysterols, which activate Smoothened in the presence of hedgehog ligand. Hedgehog ligands also interact with Hip1, Patched 2, and Gas1, which regulate the range as well as the level of hedgehog signaling. In vertebrates, Smoothened is shortened at its C-terminal end and lacks most of the phosphorylation sites of importance in Drosophila. Cos2, also of importance in Drosophila, plays no role in mammalian transduction, nor do its homologs Kif7 and Kif27. The cilium may provide a function analogous to that of Cos2 by linking Smoothened to the modulation of Gli transcription factors. Disorders associated with the hedgehog signaling network follow, including nevoid basal cell carcinoma syndrome, holoprosencephaly, Smith–Lemli–Opitz syndrome, Greig cephalopolysyndactyly syndrome, Pallister–Hall syndrome, Carpenter syndrome, and Rubinstein–Taybi syndrome. © 2010 Wiley-Liss, Inc.