title: Functional Requirements for Heparan Sulfate Biosynthesis in Morphogenesis and Nervous System Development in C. elegans.
abstract: The regulation of cell migration is essential to animal development and physiology. Heparan sulfate proteoglycans shape the interactions of morphogens and guidance cues with their respective receptors to elicit appropriate cellular responses. Heparan sulfate proteoglycans consist of a protein core with attached heparan sulfate glycosaminoglycan chains, which are synthesized by glycosyltransferases of the exostosin (EXT) family. Abnormal HS chain synthesis results in pleiotropic consequences, including abnormal development and tumor formation. In humans, mutations in either of the exostosin genes EXT1 and EXT2 lead to osteosarcomas or multiple exostoses. Complete loss of any of the exostosin glycosyltransferases in mouse, fish, flies and worms leads to drastic morphogenetic defects and embryonic lethality. Here we identify and study previously unavailable viable hypomorphic mutations in the two C. elegans exostosin glycosyltransferases genes, rib-1 and rib-2. These partial loss-of-function mutations lead to a severe reduction of HS levels and result in profound but specific developmental defects, including abnormal cell and axonal migrations. We find that the expression pattern of the HS copolymerase is dynamic during embryonic and larval morphogenesis, and is sustained throughout life in specific cell types, consistent with HSPGs playing both developmental and post-developmental roles. Cell-type specific expression of the HS copolymerase shows that HS elongation is required in both the migrating neuron and neighboring cells to coordinate migration guidance. Our findings provide insights into general principles underlying HSPG function in development.
authors.affiliation: Department of Neurobiology, UMass Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Cassandra R
authors.initials: CR
authors.lastname: Blanchette
authors.affiliation: Department of Neurobiology, UMass Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Thackeray
authors.affiliation: Department of Neurobiology, UMass Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Paola N
authors.initials: PN
authors.lastname: Perrat
authors.affiliation: Department of Biology, McGill University, Montreal, Canada.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hekimi
authors.affiliation: Department of Neurobiology, UMass Medical School, Worcester, Massachusetts, United States of America.|Department of Biological Sciences, University of Quebec at Montreal, Montreal, Canada.
authors.forename: Claire Y
authors.initials: CY
authors.lastname: Bénard
mesh_terms: D000818:Animals; D000071437:Axon Guidance; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D006497:Heparan Sulfate / Q000096:biosynthesis* / Q000235:genetics; D009024:Morphogenesis; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D006497:Heparan Sulfate; D017351:N-Acetylglucosaminyltransferases; D025521:Tumor Suppressor Proteins; C518898:Rib-1 protein, C elegans; C429019:Rib-2 protein, C elegans