Our study demonstrates that, in Xenopus embryos, DS-epi1 is important for the formation of isolated IdoA moieties interspersed with unmodified GlcA residues. This result is noteworthy because previous findings in Dse-null mice (Maccarana et al., 2009) and a human patient with Dse loss-of-function (Müller et al., 2013) have suggested that DS-epi1 is mainly responsible for the biosynthesis of IdoA blocks. The amount and arrangement of IdoA residues in CS/DS chains depends on the protein core, tissue type and signaling status (Trowbridge and Gallo, 2002; Thelin et al., 2013). Our work comprises the first investigation to demonstrate in vivo that isolated IdoA residues change the biological properties of CS/DS PGs. Even a single IdoA is thought to render the CS/DS chain more flexible, which increases its ability to interact with growth factors and matrix components. For example, CS/DS chains isolated from embryonic pig brains contain sequences with a single IdoA residue that interacts with the growth factor pleiotrophin (Bao et al., 2005).
