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The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane.

Jacobson C, Côté PD, Rossi SG, Rotundo RL, Carbonetto S - J. Cell Biol. (2001)

Bottom Line: The dystrophin-associated protein (DAP) complex spans the sarcolemmal membrane linking the cytoskeleton to the basement membrane surrounding each myofiber.These results suggest that dystroglycan is essential for the assembly of a synaptic basement membrane, most notably by localizing AChE through its binding to perlecan.In addition, they suggest that dystroglycan functions in the organization and stabilization of AChR clusters, which appear to be mediated through its binding of laminin.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, McGill University/Center for Neuroscience Research, Montréal General Hospital Research Institute, Montréal, Québec H3G 1A4, Canada.

ABSTRACT
The dystrophin-associated protein (DAP) complex spans the sarcolemmal membrane linking the cytoskeleton to the basement membrane surrounding each myofiber. Defects in the DAP complex have been linked previously to a variety of muscular dystrophies. Other evidence points to a role for the DAP complex in formation of nerve-muscle synapses. We show that myotubes differentiated from dystroglycan-/- embryonic stem cells are responsive to agrin, but produce acetylcholine receptor (AChR) clusters which are two to three times larger in area, about half as dense, and significantly less stable than those on dystroglycan+/+ myotubes. AChRs at neuromuscular junctions are similarly affected in dystroglycan-deficient chimeric mice and there is a coordinate increase in nerve terminal size at these junctions. In culture and in vivo the absence of dystroglycan disrupts the localization to AChR clusters of laminin, perlecan, and acetylcholinesterase (AChE), but not rapsyn or agrin. Treatment of myotubes in culture with laminin induces AChR clusters on dystroglycan+/+, but not -/- myotubes. These results suggest that dystroglycan is essential for the assembly of a synaptic basement membrane, most notably by localizing AChE through its binding to perlecan. In addition, they suggest that dystroglycan functions in the organization and stabilization of AChR clusters, which appear to be mediated through its binding of laminin.

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Nerve terminal size correlates with AChR distribution in dystroglycan-deficient chimeric mice. Longitudinal sections from wild-type (A and A′) and chimeric mice (B and B′) were stained with TRITC–α-Btx and antisynaptophysin antisera to label nerve terminals. Synaptophysin staining and AChR aggregates were found to be in precise alignment at synapses in both wild-type and dystroglycan-deficient muscle, whereas nerve terminals on dystroglycan-deficient myofibers appeared enlarged (compare A and A′ with B and B′). Bar, 10 μm.
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Figure 9: Nerve terminal size correlates with AChR distribution in dystroglycan-deficient chimeric mice. Longitudinal sections from wild-type (A and A′) and chimeric mice (B and B′) were stained with TRITC–α-Btx and antisynaptophysin antisera to label nerve terminals. Synaptophysin staining and AChR aggregates were found to be in precise alignment at synapses in both wild-type and dystroglycan-deficient muscle, whereas nerve terminals on dystroglycan-deficient myofibers appeared enlarged (compare A and A′ with B and B′). Bar, 10 μm.

Mentions: In dystroglycan-deficient muscle the size of the nerve terminal, as shown by immunohistochemistry for the synaptic vesicle protein synaptophysin, was also affected (Fig. 9). When compared with wild-type AChR clusters and nerve terminals (Fig. 9A and A′, respectively), endplates from chimeric animals (n = 3) could be found that were larger with obviously disorganized AChR clusters (Fig. 9 B) and a similarly large area of synaptophysin staining (Fig. 9 B′). These results suggest that dystroglycan not only was necessary for the localization of several basement membrane components to the synapse, but also might directly or indirectly regulate alignment between the pre- and postsynaptic specializations.


The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane.

Jacobson C, Côté PD, Rossi SG, Rotundo RL, Carbonetto S - J. Cell Biol. (2001)

Nerve terminal size correlates with AChR distribution in dystroglycan-deficient chimeric mice. Longitudinal sections from wild-type (A and A′) and chimeric mice (B and B′) were stained with TRITC–α-Btx and antisynaptophysin antisera to label nerve terminals. Synaptophysin staining and AChR aggregates were found to be in precise alignment at synapses in both wild-type and dystroglycan-deficient muscle, whereas nerve terminals on dystroglycan-deficient myofibers appeared enlarged (compare A and A′ with B and B′). Bar, 10 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195998&req=5

Figure 9: Nerve terminal size correlates with AChR distribution in dystroglycan-deficient chimeric mice. Longitudinal sections from wild-type (A and A′) and chimeric mice (B and B′) were stained with TRITC–α-Btx and antisynaptophysin antisera to label nerve terminals. Synaptophysin staining and AChR aggregates were found to be in precise alignment at synapses in both wild-type and dystroglycan-deficient muscle, whereas nerve terminals on dystroglycan-deficient myofibers appeared enlarged (compare A and A′ with B and B′). Bar, 10 μm.
Mentions: In dystroglycan-deficient muscle the size of the nerve terminal, as shown by immunohistochemistry for the synaptic vesicle protein synaptophysin, was also affected (Fig. 9). When compared with wild-type AChR clusters and nerve terminals (Fig. 9A and A′, respectively), endplates from chimeric animals (n = 3) could be found that were larger with obviously disorganized AChR clusters (Fig. 9 B) and a similarly large area of synaptophysin staining (Fig. 9 B′). These results suggest that dystroglycan not only was necessary for the localization of several basement membrane components to the synapse, but also might directly or indirectly regulate alignment between the pre- and postsynaptic specializations.

Bottom Line: The dystrophin-associated protein (DAP) complex spans the sarcolemmal membrane linking the cytoskeleton to the basement membrane surrounding each myofiber.These results suggest that dystroglycan is essential for the assembly of a synaptic basement membrane, most notably by localizing AChE through its binding to perlecan.In addition, they suggest that dystroglycan functions in the organization and stabilization of AChR clusters, which appear to be mediated through its binding of laminin.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, McGill University/Center for Neuroscience Research, Montréal General Hospital Research Institute, Montréal, Québec H3G 1A4, Canada.

ABSTRACT
The dystrophin-associated protein (DAP) complex spans the sarcolemmal membrane linking the cytoskeleton to the basement membrane surrounding each myofiber. Defects in the DAP complex have been linked previously to a variety of muscular dystrophies. Other evidence points to a role for the DAP complex in formation of nerve-muscle synapses. We show that myotubes differentiated from dystroglycan-/- embryonic stem cells are responsive to agrin, but produce acetylcholine receptor (AChR) clusters which are two to three times larger in area, about half as dense, and significantly less stable than those on dystroglycan+/+ myotubes. AChRs at neuromuscular junctions are similarly affected in dystroglycan-deficient chimeric mice and there is a coordinate increase in nerve terminal size at these junctions. In culture and in vivo the absence of dystroglycan disrupts the localization to AChR clusters of laminin, perlecan, and acetylcholinesterase (AChE), but not rapsyn or agrin. Treatment of myotubes in culture with laminin induces AChR clusters on dystroglycan+/+, but not -/- myotubes. These results suggest that dystroglycan is essential for the assembly of a synaptic basement membrane, most notably by localizing AChE through its binding to perlecan. In addition, they suggest that dystroglycan functions in the organization and stabilization of AChR clusters, which appear to be mediated through its binding of laminin.

Show MeSH
Related in: MedlinePlus