Loss of the Heparan Sulfate Proteoglycan Glypican5 facilitates long range Shh signaling

As a morphogen, Sonic Hedgehog (Shh) mediates signaling at a distance from its sites of synthesis. After secretion, Shh must traverse a distance through the extracellular matrix (ECM) to reach the target cells and activate the Hh response. Extracellular matrix proteins, in particular the Heparan Sulfate Proteoglycans (HSPGs) of the Glypican family have both negative and positive effects on non-cell autonomous Shh signaling, all attributed to their ability to bind Shh. Using mouse embryonic stem cell-derived mosaic tissues with compartments that lack the glycosyltransferases Exostosin1 (Ext1) and Exostosin2 (Ext2), or the HSPG core protein Glypican5 we show that cells surrounded by a mutated extracellular matrix are highly proficient distributing Shh. In contrast, cells that lack Ext1 function poorly secrete Shh. Our results confirm earlier observations that HSPGs can have both positive (Shh export) and negative influences (Shh distribution), and are supporting a model in which Shh presented on the cell surface in the context of HSPGs preferentially distributes into ECM that lacks HSPGs, possibly due to the absence of Shh sequestering molecules.