When structure matters – how heparan sulfate epimerization affects animal development

Abstract

Animal development requires concerted actions of different signaling molecules in order to ensure correctly timed and localized growth and differentiation of tissues. The extracellular matrix often provides guiding cues for signaling proteins such as the glycosaminoglycan heparan sulfate (HS), which is an important regulator of development. HS biosynthesis is a complex series of events, including chain initiation, chain elongation and chain modification. Chain modification comprises N -deacetylation of the N -acetyl-glucosamin (GlcNAc) residues, epimerization of D-glucuronic acid (GlcA) residues to L-iduronic acid (IdoA) and O -sulfation of all sugar units at different positions. None of these reactions is performed to completion along the HS chain, generating cell-type specific patterns of sulfation. It is well-known that loss of HS leads to severe developmental defects and during recent years it has become evident that even alterations in the HS sulfation pattern strongly affect animal development. Interestingly, these patterns do not only depend on the expression of the respective sulfotransferases, but are also strongly affected by N -deacetylation and epimerization of the HS chains. This review focuses on recent work on the HS C5-glucuronyl epimerase (protein GLCE, gene Glce , earlier named Hsepi ) in mouse cartilage development and relates these findings to earlier studies on GLCE function. The sulfation pattern of HS was altered in all Glce deficient tissues, but extent and nature of the changes were different between cell types. In addition, loss of Glce affected multiple signaling pathways depending on the cell type, stressing the importance of HS as a general regulator during animal development. Promoting ligand/receptor interactions as well as shaping morphogen gradients, two important roles of HS, are clearly affected by the loss of Glce in these studies and are further discussed here.