Heparan sulfate is essential for neuron migration and axon outgrowth in Caenorhabditis elegans

Abstract

Introduction The importance of heparan sulfate proteoglycans (HSPGs) has been highlighted by a number of human genetic disorders associated with mutations in genes encoding for HSPG protein cores or biosynthetic enzymes required for heparan sulfate assembly.Materials and methods We have studied the role of HS and HSPGs in the nervous system development using the nematode Caenorhabditis elegans as a model organism. Our focus has been on the single C. elegans homologues of the vertebrate syndecans, sdn‐1 and heparan 2‐O‐sulfotransferase, hst‐2.Results and discussion C. elegans syndecan, sdn‐1 and heparan 2‐O‐sulfotransferase, hst‐2, expressions coincide with the start of morphogenesis in mid‐embryonic stages after most cell divisions have occurred. Sdn‐1 is expressed primarily in neuronal cells, whereas hst‐2 is more widely expressed in neurons, hypodermis (epidermis), pharynx and the gonad leader cells (DTC). A deletion mutant of sdn‐1 which lacks the putative heparan sulfate (HS) attachment sites has specific neuron migration and axon pathfinding defects. Hst‐2 mutants have partially overlapping yet diverse neuronal migration defects. In both sdn‐1 and hst‐2 mutants, the serotonergic hermaphrodite‐specific neurons (HSNs) fail to migrate to their correct position in the vicinity of the vulva and hence fail to innervate the vulval muscles causing sdn‐1 and hst‐2 mutants to become egg‐laying defective (egl) and accumulate embryos within the mother. Canal‐associated neurons (CANs) that, like the HSNs, have a stereotyped long‐distance postembryonic migration pattern also fail to migrate to their correct position in sdn‐1 mutants, whereas in hst‐2 mutants the CANs migrate normally. These results suggest that specific 2‐O‐sulfation of sdn‐1 HS is essential for HSN migration, whereas it is dispensable for CAN migration.Hst‐2 mutants have additional cell migration defects that are not detected in sdn‐1 mutants suggesting that other HSPGs such as perlecan/unc‐52 and glypican/gpn‐1 may be responsible for these defects.