title: Extracellular sugar modifications provide instructive and cell-specific information for axon-guidance choices.
abstract: Heparan sulfates (HSs) are extraordinarily complex extracellular sugar molecules that are critical components of multiple signaling systems controlling neuronal development. The molecular complexity of HSs arises through a series of specific modifications, including sulfations of sugar residues and epimerizations of their glucuronic acid moieties. The modifications are introduced nonuniformly along protein-attached HS polysaccharide chains by specific enzymes. Genetic analysis has demonstrated the importance of specific HS-modification patterns for correct neuronal development. However, it remains unclear whether HS modifications provide a merely permissive substrate or whether they provide instructive patterning information during development. We show here with single-cell resolution that highly stereotyped motor axon projections in C. elegans depend on specific HS-modification patterns. By manipulating extracellular HS-modification patterns, we can cell specifically reroute axons, indicating that HS modifications are instructive. This axonal rerouting is dependent on the HS core protein lon-2/glypican and both the axon guidance cue slt-1/Slit and its receptor eva-1. These observations suggest that a changed sugar environment instructs slt-1/Slit-dependent signaling via eva-1 to redirect axons. Our experiments provide genetic in vivo evidence for the "HS code" hypothesis which posits that specific combinations of HS modifications provide specific and instructive information to mediate the specificity of ligand/receptor interactions.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA. hbuelow@aecom.yu.edu
authors.forename: Hannes E
authors.initials: HE
authors.lastname: Bülow
authors.forename: Nartono
authors.initials: N
authors.lastname: Tjoe
authors.forename: Robert A
authors.initials: RA
authors.lastname: Townley
authors.forename: Dominic
authors.initials: D
authors.lastname: Didiano
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.forename: Oliver
authors.initials: O
authors.lastname: Hobert
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D019521:Body Patterning / Q000502:physiology; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D017238:Genes, Helminth; D006497:Heparan Sulfate / Q000235:genetics / Q000378:metabolism*; D008959:Models, Neurological; D009046:Motor Neurons / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D006497:Heparan Sulfate; D009419:Nerve Tissue Proteins; C523438:EVA-1 protein, C elegans; C492285:slt-1 protein, C elegans