The HSPG Syndecan is a core organizer of cholinergic synapses inC. elegans

Abstract

SUMMARYThe extracellular matrix has emerged as an active component of chemical synapses regulating synaptic formation, maintenance and homeostasis. The heparan sulfate proteoglycan syndecans are known to regulate cellular and axonal migration in the brain. They are also enriched at synapses, but their synaptic functions remain more elusive. Here we show that SDN-1, the sole ortholog of syndecan in C. elegans, is absolutely required for the synaptic clustering of homomeric α7-like N-acetylcholine receptors (AChR) and regulates the synaptic content of heteromeric L-AChRs. SDN-1 is concentrated at neuromuscular junctions (NMJs) by the neurally-secreted synaptic organizer Ce-Punctin/MADD-4, which also activates the transmembrane netrin receptor DCC. Those cooperatively recruit the FARP and CASK orthologues that localize N-AChRs at cholinergic NMJs through physical interactions. Therefore, SDN-1 stands at the core of the cholinergic synapse organization by bridging the extracellular synaptic determinants to the intracellular synaptic scaffold that controls the postsynaptic receptor content.

Toolkits for detailed and high-throughput interrogation of synapses inC. elegans

“…These tools have been somewhat constrained by the relative paucity of cell-specific promoters, but recent single cell RNA-sequencing studies (Taylor et al 2021, Packer et al 2019) have yielded novel cell-specific promoters for driving fluorescent proteins in neurons which previously lacked sparseexpressing genes. Moreover, the relative ease of labeling endogenous genetic loci with a fluorophore using CRISPR/Cas9 (Eroglu, Yu, and Derry, 2023;Ghanta et al, 2021;Ghanta and Mello, 2020) has led to an increase in reporters with fluorophore-tagged proteins localized at chemical and electrical synapses (Zhou et al, 2021;Bhattacharya et al, 2019;Lipton, Maeder, and Shen, 2018;Tu et al, 2015;Pinan-Lucarré et al, 2014). With these advances over the years, the C. elegans community has built a growing, but still very limited, collection of synaptic reporters.…”

Loss of the extracellular matrix protein DIG-1 causes glial fragmentation, dendrite breakage, and dendrite extension defects

“…Briefly, the morphology of every neuron and glial cell is highly stereotyped and has been carefully catalogued; individual cells can be readily visualized in live intact animals throughout life; and it is straightforward to perform forward genetic screens by visually identifying mutants that show aberrant morphology of single neurons or glial cells. Recent screens have revealed roles for extracellular factors in diverse aspects of neurodevelopment, including neuroblast migration [2][3][4], axon and dendrite extension [5][6][7][8][9], fasciculation of neurites into nerve bundles [10][11][12][13][14][15], and synapse development [16][17][18][19][20][21].…”