PMID:11389830

Citation	Lewis, PM, Dunn, MP, McMahon, JA, Logan, M, Martin, JF, St-Jacques, B and McMahon, AP (2001) Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell 105:599-612
Abstract	Sonic hedgehog (Shh) signaling from the posterior zone of polarizing activity (ZPA) is the primary determinant of anterior-posterior polarity in the vertebrate limb field. An active signal is produced by an autoprocessing reaction that covalently links cholesterol to the N-terminal signaling moiety (N-Shh(p)), tethering N-Shh(p) to the cell membrane. We have addressed the role played by this lipophilic modification in Shh-mediated patterning of mouse digits. Both the distribution and activity of N-Shh(p) indicate that N-Shh(p) acts directly over a few hundred microns. In contrast, N-Shh, a form that lacks cholesterol, retains similar biological activity to N-Shh(p), but signaling is posteriorly restricted. Thus, cholesterol modification is essential for the normal range of signaling. It also appears to be necessary for appropriate modulation of signaling by the Shh receptor, Ptc1.
Links	PubMed
Keywords	Animals; Basic Helix-Loop-Helix Transcription Factors; Body Patterning/physiology; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins/genetics; Bone Morphogenetic Proteins/metabolism; Chimera; Cholesterol/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Female; Fibroblast Growth Factors/genetics; Fibroblast Growth Factors/metabolism; Forelimb/embryology; Forelimb/physiology; Gene Expression Regulation, Developmental; Hedgehog Proteins; Hindlimb/embryology; Hindlimb/physiology; Homeodomain Proteins/genetics; Homeodomain Proteins/metabolism; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Kruppel-Like Transcription Factors; Limb Buds/embryology; Limb Buds/physiology; Male; Membrane Proteins; Mice; Nerve Tissue Proteins; Oncogene Proteins/genetics; Oncogene Proteins/metabolism; Phenotype; Proteins/genetics; Proteins/metabolism; Receptors, Cell Surface; Repressor Proteins; Signal Transduction/physiology; Trans-Activators; Transcription Factors/genetics; Transcription Factors/metabolism; Transforming Growth Factor beta; Xenopus Proteins; Zebrafish Proteins
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