a targeted glycan-related gene screen reveals heparan sulfate proteoglycan sulfation regulates wnt and bmp trans-synaptic signaling目标基因glycan-related屏幕显示硫酸乙酰肝素蛋白聚糖硫酸盐化作用调节wnt和bmp trans-synaptic信号.pdfVIP

A Targeted Glycan-Related Gene Screen Reveals Heparan Sulfate Proteoglycan Sulfation Regulates WNT and BMP Trans-Synaptic Signaling 1 2 2 1 Neil Dani , Minyeop Nahm , Seungbok Lee , Kendal Broadie * 1 Department of Biological Sciences and Department of Cell and Developmental Biology, Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee, United States of America, 2 Department of Cell and Developmental Biology, Seoul National University, Seoul, Republic of Korea Abstract A Drosophila transgenic RNAi screen targeting the glycan genome, including all N/O/GAG-glycan biosynthesis/modification enzymes and glycan-binding lectins, was conducted to discover novel glycan functions in synaptogenesis. As proof-of- product, we characterized functionally paired heparan sulfate (HS) 6-O-sulfotransferase (hs6st) and sulfatase (sulf1), which bidirectionally control HS proteoglycan (HSPG) sulfation. RNAi knockdown of hs6st and sulf1 causes opposite effects on functional synapse development, with decreased (hs6st) and increased (sulf1) neurotransmission strength confirmed in null mutants. HSPG co-receptors for WNT and BMP intercellular signaling, Dally-like Protein and Syndecan, are differentially misregulated in the synaptomatrix of these mutants. Consistently, hs6st and sulf1 nulls differentially elevate both WNT (Wingless; Wg) and BMP (Glass Bottom Boat; Gbb) ligand abundance in the synaptomatrix. Anterograde Wg signaling via Wg receptor dFrizzled2 C-terminus nuclear import and retrograde Gbb signaling via synaptic MAD phosphorylation and nuclear import are differentially activated in hs6st and sulf1 mutants. Consequently, transcriptional control of presynaptic glutamate release machinery and postsynaptic gluta