RRC ID 53392
Author Blanchette CR, Thackeray A, Perrat PN, Hekimi S, Bénard CY.
Title Functional Requirements for Heparan Sulfate Biosynthesis in Morphogenesis and Nervous System Development in C. elegans.
Journal PLoS Genet
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.
Volume 13(1)
Pages e1006525
Published 2017-1-1
DOI 10.1371/journal.pgen.1006525
PII PGENETICS-D-16-00800
PMID 28068429
PMC PMC5221758
MeSH Animals Axon Guidance* Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Heparitin Sulfate / biosynthesis* Heparitin Sulfate / genetics Morphogenesis* Mutation N-Acetylglucosaminyltransferases / genetics N-Acetylglucosaminyltransferases / metabolism Neurons / metabolism Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism
IF 5.175
Times Cited 6
Resource
C.elegans tm472 tm516 tm710