Differential sulfations and epimerization define heparan sulfate specificity in nervous system development.
Heparan sulfate proteoglycans (HSPG) are components of the extracellular matrix through which axons navigate to reach their targets. The heparan sulfate (HS) side chains of HSPGs show complex and differentially regulated patterns of secondary modifications, including sulfations of distinct hydroxyl groups and epimerization of an asymmetric carbon atom. These modifications endow the HSPG-containing extracellular matrix with the potential to code for an enormous molecular diversity. Attempting to decode this diversity, we analyzed C. elegans animals lacking three HS-modifying enzymes, glucuronyl C5-epimerase, heparan 6O-sulfotransferase, and 2O-sulfotransferase. Each of the mutant animals exhibit distinct as well as overlapping axonal and cellular guidance defects in specific neuron classes. We have linked individual HS modifications to two specific guidance systems, the sax-3/Robo and kal-1/Anosmin-1 systems, whose activity is dependent on different HS modifications in different cellular contexts. Our results demonstrate that the molecular diversity in HS encodes information that is crucial for different aspects of neuronal development.
Department of Biochemistry and Molecular Biophysics, Center for Neurobiology and Behavior, Columbia University, College of Physicians and Surgeons, New York, NY 10032 USA.
Hannes E
HE
Bülow
Oliver
O
Hobert
D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006497:Heparan Sulfate / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009420:Nervous System / Q000254:growth & development*; D009474:Neurons / Q000502:physiology; D019998:Racemases and Epimerases / Q000235:genetics* / Q000378:metabolism*
D006497:Heparan Sulfate; D019998:Racemases and Epimerases