title: Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1.
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.
authors.affiliation: Department of Molecular and Cellular Biology, The Biolabs, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Lewis
authors.forename: M P
authors.initials: MP
authors.lastname: Dunn
authors.forename: J A
authors.initials: JA
authors.lastname: McMahon
authors.forename: M
authors.initials: M
authors.lastname: Logan
authors.forename: J F
authors.initials: JF
authors.lastname: Martin
authors.forename: B
authors.initials: B
authors.lastname: St-Jacques
authors.forename: A P
authors.initials: AP
authors.lastname: McMahon
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D019521:Body Patterning / Q000502:physiology; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002678:Chimera; D002784:Cholesterol / Q000378:metabolism*; D016207:Cytokines; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D005552:Forelimb / Q000196:embryology / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D006614:Hindlimb / Q000196:embryology / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D018878:Limb Buds / Q000196:embryology / Q000502:physiology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D000071676:Zinc Finger Protein GLI1; D000074290:Zinc Finger Protein Gli3
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002784:Cholesterol; D016207:Cytokines; D004268:DNA-Binding Proteins; D005346:Fibroblast Growth Factors; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011506:Proteins; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D000071676:Zinc Finger Protein GLI1; D000074290:Zinc Finger Protein Gli3; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; C113178:Grem1 protein, mouse; C108003:GLI3 protein, Xenopus; C065683:GLI3 protein, human; C486400:GREM1 protein, Xenopus; C486399:GREM1 protein, human; C465571:Gli3 protein, mouse; C498766:Hand2 protein, mouse; C084118:Hoxd13 protein, mouse; C000606240:Ptch1 protein, mouse; C509239:SHH protein, human; C525812:bmp4 protein, Xenopus; C525813:bmp4 protein, zebrafish; C112971:fibroblast growth factor 14; C410915:hand2 protein, zebrafish; C491715:ptch1 protein, zebrafish