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.
Highlights
Cell migration is key to animal development and physiology
Migrating cells are guided by extracellular molecular cues, and cellular responses to these cues are regulated by heparan sulfate proteoglycans
Our analysis shows that these HSchain-elongation mutations affect the development of the nervous system as they result in misguided migrations of neurons and axons
Summary
Cell migration is key to animal development and physiology. To reach their targets, migrating cells rely on guidance factors and morphogens, which can be regulated by heparan sulfate proteoglycans (HSPGs) [1]. A number of HSPGs have been characterized in C. elegans using mutations that affect specific core proteins, such as mutations in sdn1/syndecan, lon-2/glypican, cle-1/collagen type XVIII, unc-52/perlecan, gpn-1/glypican, and agr-1/agrin [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26] These studies have uncovered precise roles of individual HSPGs in morphogenesis and nervous system development. The phenotypic consequences of such mutations in HSPG core proteins can be due to the absence of either the core protein or the HS chains, or both, making it difficult to extract the functional contribution of the HS chains per se with such analysis of HSPG core protein mutants
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