Specific heparan sulfate modifications stabilize the synaptic organizer MADD-4/Punctin at Caenorhabditis elegans neuromuscular junctions. Issue 4 (13th May 2021)

• Record Type: Journal Article
• Authors: Cizeron, Mélissa; Granger, Laure; Bülow, Hannes E; Bessereau, Jean-Louis
• Editors: Hobert, O
• Is Part Of: Genetics. Volume 218:Issue 4(2021)
• Publication Date: 2021-05-13
• Subjects: heparan sulfate modification enzymes -- synapse -- C. elegans -- 3-O-sulfotransferase -- MADD-4/Punctin -- synaptomatrix -- heparan sulfate proteoglycan -- syndecan; Genetics -- Periodicals; 576.5
• DOI: 10.1093/genetics/iyab073
• Languages: English
• ISSNs: 0016-6731

Abstract

Abstract : Heparan sulfate proteoglycans carry long sugar chains that are heavily modified by different enzymes. Specific modifications may contribute to the emerging role of heparan sulfate in synapse organization. Here, Cizeron et al . show that distinct modifications are present at excitatory and inhibitory neuromuscular junctions in Caenorhabditis elegans, potentially contributing to this sugar code. Moreover, stabilization of the synaptic organizer MADD-4/Punctin requires specific modification patterns involving 3-O-sulfation, a modification of heparan sulfate chains particularly important for sugar-protein interactions. Abstract: Heparan sulfate (HS) proteoglycans contribute to the structural organization of various neurochemical synapses. Depending on the system, their role involves either the core protein or the glycosaminoglycan chains. These linear sugar chains are extensively modified by HS modification enzymes, resulting in highly diverse molecules. Specific modifications of glycosaminoglycan chains may thus contribute to a sugar code involved in synapse specificity. Caenorhabditis elegans is particularly useful to address this question because of the low level of genomic redundancy of these enzymes, as opposed to mammals. Here, we systematically mutated the genes encoding HS modification enzymes in C. elegans and analyzed their impact on excitatory and inhibitory neuromuscular junctions (NMJs). Using single chain antibodies that recognize different HS modification patterns, we show in vivo that these two HS epitopes are carried by the SDN-1 core protein, the unique C. elegans syndecan ortholog, at NMJs. Intriguingly, these antibodies differentially bind to excitatory and inhibitory synapses, implying unique HS modification patterns at different NMJs. Moreover, while most enzymes are individually dispensable for proper organization of NMJs, we show that 3- O -sulfation of SDN-1 is required to maintain wild-type levels of the extracellular matrix protein MADD-4/Punctin, a central synaptic organizer that defines the identity of excitatory and inhibitory synaptic domains at the plasma membrane of muscle cells.