An extracellular pathway for dystroglycan function in acetylcholine receptor aggregation and laminin deposition in skeletal myotubes.
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.
Tremblay
Mathieu R
MR
Department of Biology, McGill University, Montréal General Hospital Research Institute, Montréal, Québec H3G 1A4, Canada.
Carbonetto
Salvatore
S
Department of Biology, McGill University, Montréal General Hospital Research Institute, Montréal, Québec H3G 1A4, Canada; Center for Research in Neuroscience, McGill University, Montréal General Hospital Research Institute, Montréal, Québec H3G 1A4, Canada. Electronic address: Sal.carbonetto@mcgill.ca.
D018171:Agrin / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007797:Laminin / Q000378:metabolism*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D051381:Rats; D011950:Receptors, Cholinergic / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism
D018171:Agrin; D007797:Laminin; D011950:Receptors, Cholinergic; D049030:Dystroglycans