Abstract
BackgroundThe Dystrophin-glycoprotein complex (DGC) comprises dystrophin, dystroglycan, sarcoglycan, dystrobrevin and syntrophin subunits. In muscle fibers, it is thought to provide an essential mechanical link between the intracellular cytoskeleton and the extracellular matrix and to protect the sarcolemma during muscle contraction. Mutations affecting the DGC cause muscular dystrophies. Most members of the DGC are also concentrated at the neuromuscular junction (NMJ), where their deficiency is often associated with NMJ structural defects. Hence, synaptic dysfunction may also intervene in the pathology of dystrophic muscles. Dystroglycan is a central component of the DGC because it establishes a link between the extracellular matrix and Dystrophin. In this study, we focused on the synaptic role of Dystroglycan (Dg) in Drosophila.Methodology/Principal FindingsWe show that Dg was concentrated postsynaptically at the glutamatergic NMJ, where, like in vertebrates, it controls the concentration of synaptic Laminin and Dystrophin homologues. We also found that synaptic Dg controlled the amount of postsynaptic 4.1 protein Coracle and alpha-Spectrin, as well as the relative subunit composition of glutamate receptors. In addition, both Dystrophin and Coracle were required for normal Dg concentration at the synapse. In electrophysiological recordings, loss of postsynaptic Dg did not affect postsynaptic response, but, surprisingly, led to a decrease in glutamate release from the presynaptic site.Conclusion/SignificanceAltogether, our study illustrates a conservation of DGC composition and interactions between Drosophila and vertebrates at the synapse, highlights new proteins associated with this complex and suggests an unsuspected trans-synaptic function of Dg.
Highlights
In muscle fibers, the Dystrophin-glycoprotein complex (DGC) is thought to provide an essential mechanical link between the intracellular cytoskeleton and the extracellular matrix
In order to identify proteins of the Dystrophin-glycoprotein complex conserved at the Drosophila neuromuscular junction (NMJ), and to study these molecules in a model organism, we undertook a screen of many antibodies directed against mammalian DGC proteins, for a specific staining at the third instar larval NMJ
This indicated that the antibody staining at the NMJ was specific, and that Dg was expressed in the muscles
Summary
The Dystrophin-glycoprotein complex (DGC) is thought to provide an essential mechanical link between the intracellular cytoskeleton and the extracellular matrix. This complex comprises Dystroglycan subunits (a and b), Dystrophin or Utrophin, sarcoglycans subunits, syntrophin subunits, and dystrobrevin subunits. The extracellular Dg a-subunit is heavily glycosylated, and interacts with extracellular Laminin, whereas the transmembrane b-subunit interacts with subsarcolemmal Dystrophin, which itself links the actin network The maintenance of this structural link provides stability of the sarcolemma, especially upon muscle contraction. In Duchenne muscular dystrophy, mutation and subsequent loss of Dystrophin destabilizes the other DGC members [4], which further leads to mechanical damage of the muscle cell membrane [5,6]. We focused on the synaptic role of Dystroglycan (Dg) in Drosophila
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