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

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, ␣-and ␤-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 ␤-DG in myotubes derived from wild-type embryonic stem cells or from cells null for DG. We show that ␣-DG is properly glycosylated and targeted to the myotube surface in the absence of ␤-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 ␣-and ␤-DG in skeletal muscle may coordinate independent roles in signaling. We discuss how DG may regulate synapses through extracellular signaling functions of its ␣ subunit.

A Putative Src Homology 3 Domain Binding Motif but Not the C-terminal Dystrophin WW Domain Binding Motif Is Required for Dystroglycan Function in Cellular Polarity in Drosophila

“…4D; Table 1), indicating that, as discussed earlier, the Dg extracellular domain alone might function in some capacity to regulate egg chamber growth. This is similar to what is seen with skeletal myotubes (39). DC2 and 4P, however, rescued egg chamber growth at the same level as the FL (Fig.…”

“…Nevertheless, in all the assays described, some phenotypes above the control level were observed even with the constructs that lack most of the C-terminal domain (C1; Fig. 3, F-H), indicating that the Dg extracellular domain alone might function in some capacity to regulate cellular polarity (similar to seen in other systems (30,39).…”

Dystroglycan expression is reduced during prostate tumorigenesis and is regulated by androgens in prostate cancer cells

“…6). These findings are not surprising in view of recent evidence suggesting that b-DG might have independent functions in organizing cell surface proteins (Kahl and Campanelli, 2003;Driss et al, 2006;Tremblay and Carbonetto, 2006). Thus, an increased expression level of b-DG subunit might be per se able to promote, directly and/or indirectly (i.e., stabilizing other adhesion molecules), cell adhesion.…”

Making muscle: skeletal myogenesisin vivoandin vitro

“…The dystrophin-associated glycoprotein complex (DGC), which links the myofiber cytoskeleton to the basal lamina through the sarcolemma, is also assembled in vitro. DGC components, including dystrophin (Chal et al, 2015;Ozasa et al, 2007), dystroglycan and integrins (Hirsch et al, 1998;Jacobson et al, 2001;Tremblay and Carbonetto, 2006), were found distributed at the sarcolemma of PSC-derived myofibers (Fig. 5, Tables S1 and S2).…”

“…Patch clamp and gene expression analyses of mESC-derived myotubes have shown that this developmental transition can also occur in vitro, as these cells start to express the adult AchRε after 2 weeks of differentiation (Guan et al, 1999;Jacobson et al, 2001;Rohwedel et al, 1998bRohwedel et al, , 1994Tremblay and Carbonetto, 2006) (Fig. 5B).…”