There is increasing evidence that heparan sulfate (HS) plays an essential role in various axon guidance processes. These observations, however, have not addressed whether HS is required cell autonomously as an axonal coreceptor or as an environmental factor that modulates the localization of guidance molecules in the terrain in which growing axons navigate. Here we demonstrate that netrin-1-mediated commissural axon guidance requires cell-autonomous expression of HS in commissural neuronsin vivo. We used theWnt1 –Cretransgene to drive region-specific ablation ofExt1, which encodes an enzyme essential for HS synthesis, in the dorsal part of the spinal cord. Remarkably,Wnt1–Cre-mediated ablation ofExt1causes commissural axon pathfinding defects that share similarities with those ofNetrin-1-deficient andDCC(deleted in colorectal cancer)-deficient mice. NeitherExt1-deficient dorsal spinal cord explants nor wild-type explants in which HS expression was ablated could extend axons in response to netrin-1. Intracellular signaling downstream of netrin-1 and DCC was defective inExt1-deficient commissural neurons and in DCC-transfected HEK293T cells from which HS was removed. These results demonstrate that the expression of HS by commissural neurons is essential for these neurons to transduce netrin-1 signals, thus providing evidence for a cell-autonomous role of HS in netrin-1/DCC-mediated axon guidance.

Matsumoto, Y., Irie, F., Inatani, M., Tessier-Lavigne, M., & Yamaguchi, Y. (2007). Netrin-1/DCC Signaling in Commissural Axon Guidance Requires Cell-Autonomous Expression of Heparan Sulfate. The Journal of Neuroscience, 27(16), 4342–4350.