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ACS Chem Neurosci. 2018 Aug 28. doi: 10.1021/acschemneuro.8b00295. [Epub ahead of print]

Influencing Early Stages of Neuromuscular Junction Formation through Glycocalyx Engineering.

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1
Department of Chemistry and Biochemistry , University of California, San Diego , 9500 Gilman Drive , La Jolla , California 92093-0358 , United States.

Abstract

Achieving molecular control over the formation of synaptic contacts in the nervous system can provide important insights into their regulation and can offer means for creating well-defined in vitro systems to evaluate modes of therapeutic intervention. Agrin-induced clustering of acetylcholine receptors (AChRs) at postsynaptic sites is a hallmark of the formation of the neuromuscular junction, a synapse between motoneurons and muscle cells. In addition to the cognate agrin receptor LRP4 (low-density lipoprotein receptor related protein-4), muscle cell heparan sulfate (HS) glycosaminoglycans (GAGs) have also been proposed to contribute to AChR clustering by acting as agrin co-receptors. Here, we provide direct evidence for the role of HS GAGs in agrin recruitment to the surface of myotubes, as well as their functional contributions toward AChR clustering. We also demonstrate that engineering of the myotube glycocalyx using synthetic HS GAG polymers can replace native HS structures to gain control over agrin-mediated AChR clustering.

KEYWORDS:

AChR clustering; agrin; glycocalyx engineering; heparan sulfate; neuromuscular junction

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