Functional Requirements for Heparan Sulfate Biosynthesis in Morphogenesis and Nervous System Development in C. elegans
Student Authors
Cassandra BlanchettePaola Perrat
Academic Program
NeuroscienceUMass Chan Affiliations
Graduate School of Biomedical Sciences, Neuroscience ProgramBenard Lab
Neurobiology
Document Type
Journal ArticlePublication Date
2017-01-09
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Show full item recordAbstract
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.Source
PLoS Genet. 2017 Jan 9;13(1):e1006525. doi: 10.1371/journal.pgen.1006525. eCollection 2017. Link to article on publisher's siteDOI
10.1371/journal.pgen.1006525Permanent Link to this Item
http://hdl.handle.net/20.500.14038/37929PubMed ID
28068429Related Resources
Link to Article in PubMedRights
Copyright: © 2017 Blanchette et al.Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1371/journal.pgen.1006525
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Except where otherwise noted, this item's license is described as Copyright: © 2017 Blanchette et al.