Co-receptor function of heparan sulfate in Slit3-Robo4 signaling: Heparan sulfate, carried by the heparan sulfate proteoglycans, such as syndecan, binds Slit3 on wildtype endothelial cell surface to form the heparan sulfate-Slit3-Robo4 ternary complexes facilitating Slit3-Robo4 signaling. Genetic ablation of N-deacetylase-N-sulfotransferase-1 (Ndst1), an dual function enzyme that initiates modification reactions during heparan sulfate biosynthesis, reduces the sulfation modifications, leading to Ndst1-/- endothelial heparan sulfate fails to bind Slit3 and disrupt heparan sulfate-Slit3-Robo4 complex formation and the subsequent angiogenic signaling.
Zhang B, Xiao WY, Qiu H, Zhang FM, Moniz HA Condac E, Gutierrez-Sanchez G, Heiss C, Clugston RD, Azadi P, Greer JJ, Bergmann C, Moremen KW, Li D, Linhardt RJ, Esko JD, Wang L (2014). Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia. J Clin Invest. 124(1):209-221. [PMC3871243]