title: Hedgehog lipid modifications are required for Hedgehog stabilization in the extracellular matrix.
abstract: The Hedgehog (Hh) family of morphogenetic proteins has important instructional roles in metazoan development. Despite Hh being modified by Ct-cholesterol and Nt-palmitate adducts, Hh migrates far from its site of synthesis and programs cellular outcomes, depending on its local concentrations. We show that in the receiving cells of the Drosophila wing imaginal disc, lipid-unmodified Hh spreads across many more cell diameters than the wild type and this spreading leads to the activation of low but not high threshold responses. Unlipidated Hh forms become internalized through the apical plasma membrane, while wild-type Hh enters through the basolateral cell surface - in all cases via a dynamin-dependent mechanism. Full activation of the Hh pathway and the spread of Hh throughout the extracellular matrix depend on the ability of lipid-modified Hh to interact with heparan sulfate proteoglycans (HSPG). However, neither Hh-lipid modifications nor HSPG function are required to activate the targets that respond to low levels of Hh. All these data show that the interaction of lipid-modified Hh with HSPG is important both for precise Hh spreading through the epithelium surface and for correct Hh reception.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, CSIC, Universidad Autónoma de Madrid, Cantoblanco, Spain.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Callejo
authors.forename: Carlos
authors.initials: C
authors.lastname: Torroja
authors.forename: Luis
authors.initials: L
authors.lastname: Quijada
authors.forename: Isabel
authors.initials: I
authors.lastname: Guerrero
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000196:embryology* / Q000502:physiology; D004628:Embryonic Structures / Q000033:anatomy & histology / Q000378:metabolism; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism*; D017930:Genes, Reporter; D053823:Hedgehog Proteins; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019076:Transgenes; D014921:Wings, Animal / Q000033:anatomy & histology / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D019812:Heparan Sulfate Proteoglycans; D008055:Lipids; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; C113073:TTV protein, Drosophila; C077245:hh protein, Drosophila