Abstract
Neuromuscular junction (NMJ) formation involves morphological changes both in motor terminals and muscle membrane. The molecular mechanisms leading to NMJ formation and maintenance have not yet been fully elucidated. During the last decade, it has become clear that virtually all cells release different types of extracellular vesicles (EVs), which can be taken up by nearby or distant cells modulating their activity. Initially, EVs were associated to a mechanism involved in the elimination of unwanted material; subsequent evidence demonstrated that exosomes, and more in general EVs, play a key role in intercellular communication by transferring proteins, lipids, DNA and RNA to target cells. Recently, EVs have emerged as potent carriers for Wnt, bone morphogenetic protein, miRNA secretion and extracellular traveling. Convincing evidence demonstrates that presynaptic terminals release exosomes that are taken up by muscle cells, and these exosomes can modulate synaptic plasticity in the recipient muscle cell in vivo. Furthermore, recent data highlighted that EVs could also be a potential cause of neurodegenerative disorders. Indeed, mutant SOD1, TDP-43 and FUS/TLS can be secreted by neural cells packaged into EVs and enter in neighboring neural cells, contributing to the onset and severity of the disease.
Highlights
The neuromuscular junction (NMJ) is a chemical synapse formed between motoneurons and skeletal muscles and is covered by Schwann cells (SCs)
According to the International Society for Extracellular Vesicles, three main types of extracellular vesicles (EVs) have been described based on their mechanism of release and size: exosomes are less than 150 nm in diameter, while microvesicles/shedding particles and apoptotic bodies are both considered to be larger than 100 nm [46]
As a matter of fact, Wnts can be internalized as well as secreted via microglia, Pioneering studies on Neuromuscular junction (NMJ) establishment in Drosophila have paved the way for our understanding of the contribution of EVs to the delivery of Wnts from neural presynaptic to postsynaptic muscle as documented by Kerr et al [56], who showed that glia-derived Wg regulates the localization of glutamate receptors at postsynaptic sites of the NMJ
Summary
The neuromuscular junction (NMJ) is a chemical synapse formed between motoneurons and skeletal muscles and is covered by Schwann cells (SCs). The binding of Wnts to Fz receptors and Lrp5/6 activates dishevelled (Dvl), which inhibits glycogen synthase kinase-3 β (Gsk-3β), leading to the disassembly of axin destruction complex (formed by Gsk-3β, axin, adenomatous polyposis coli protein (APC) and β-catenin) This results in the inhibition of β-catenin phosphorylation and its accumulation in the cytoplasm [27,28,29,30], followed by β-catenin translocation to the nucleus to regulate gene expression. In line with these data, BMPs expressed by muscle cells exert autocrine effects, but could be involved in the modulation of motor neuron behavior This hypothesis is consistent with the crucial role that the retrograde secretion of the BMP ligand glass bottom boat (Gbb) plays on the nerve terminal development and NMJ establishment in Drosophila [39]. In the NMJ development and growth, in vivo evidence points out an anterograde action of Wnt signals on postsynaptic differentiation, whereas BMP ligands likely act through retrograde mechanisms to induce presynaptic effects
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