In vivo activities of heparan sulfate differentially modified by NDSTs during development.

Heparan sulfate proteoglycans (HSPGs) serve as co-receptors for growth factor signaling during development. It is well known that the level and patterns of sulfate groups of heparan sulfate (HS) chains, or HS fine structures, have a major impact on HSPG function. On the other hand, the physiological significance of other structural features of HS, including NS/NA domain organization, remains to be elucidated. A blueprint of the HS domain structures is mainly controlled by HS -deacetylase/-sulfotransferases (NDSTs). To analyze in vivo activities of differentially modified HS, we established two knock-in (KI) strains with the insertion of mouse () or () in the locus of (), the only NDST. In these KI lines, mNDSTs are expressed from the locus, in the level and patterns identical to the endogenous gene. Thus, phenotypes of KI and KI animals reflect the ability of HS structures made by these enzymes to rescue mutation. Remarkably, we found that completely rescued the loss of showed a limited rescue ability, despite a higher level of HS sulfation compared to HS in KI. Our study suggests that independent of sulfation levels, additional HS structural features controlled by NDSTs play key roles during tissue patterning.