An Extracellular Pathway for Dystroglycan Function in Acetylcholine Receptor Aggregation and Laminin Deposition in Skeletal Myotubes

Mathieu R Tremblay,Salvatore Carbonetto

doi:10.1074/jbc.m600912200

Mathieu R Tremblay, Salvatore Carbonetto

Open Access

https://doi.org/10.1074/jbc.m600912200

Copy DOI

Abstract

The dystroglycan (DG) complex is involved in agrin-induced acetylcholine receptor clustering downstream of muscle-specific kinase where it regulates the stability of acetylcholine receptor aggregates as well as assembly of the synaptic basement membrane. We have previously proposed that this entails coordinate extracellular and intracellular interactions of its two subunits, alpha- and beta-DG. To assess the contribution of the extracellular and intracellular portions of DG, we have used adenoviruses to express full-length and deletion mutants of beta-DG in myotubes derived from wild-type embryonic stem cells or from cells null for DG. We show that alpha-DG is properly glycosylated and targeted to the myotube surface in the absence of beta-DG. Extracellular interactions of DG modulate the size and the microcluster density of agrin-induced acetylcholine receptor aggregates and are responsible for targeting laminin to these clusters. Thus, the association of alpha- and beta-DG in skeletal muscle may coordinate independent roles in signaling. We discuss how DG may regulate synapses through extracellular signaling functions of its alpha subunit.

Highlights

In skeletal muscle, the absence of DG leads to muscular dystrophy [12, 13]
We proposed that ␣- and ␤-DG function coordinately to assemble an extracellular and intracellular matrix of proteins [38], which is consistent with a recent report suggesting novel extracellular interactions for DG [39]
A simple model for DG function predicts that extracellular interactions mediated by ␣-DG would in turn signal intracellularly via ␤-DG

Summary

Dystroglycan in Neuromuscular Junction Formation

DG constructs consisting of ␣-DG alone or of ␣-DG and the extracellular regions of ␤-DG can regulate aspects of AChR aggregation, namely the size of AChR aggregates, the distribution of microclusters within them, and the assembly of laminin at these aggregates. The implications of these observations for synapse formation and signaling via DG are discussed

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION