Electrophysiology of the neuromuscular junction of the laminin-2 (merosin) deficient C57 BL/6J dy2J/dy2J dystrophic mouse

Edwards, Jonathan P.; Hatton, Paul; Wareham, Anthony C.

doi:10.1016/s0006-8993(98)00010-9

Cited by 12 publications

(9 citation statements)

References 36 publications

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“…3, B-D). Laminin-11 promotes presynaptic differentiation and repels Schwann cell processes; laminin-9 promotes the precise alignment of pre-and postsynaptic specializations; and laminin-4 may be important for structural integrity, as is ␣2-containing laminin-2 extrasynaptically (30,46,56,57). Thus, three members of the same gene family collaborate to promote, organize, and maintain presynaptic differentiation.…”

Section: Differentiation Of Nerve Terminalsmentioning

confidence: 99%

The Basement Membrane/Basal Lamina of Skeletal Muscle

Sanes

2003

Journal of Biological Chemistry

377

311

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Section: Differentiation Of Nerve Terminalsmentioning

confidence: 99%

The Basement Membrane/Basal Lamina of Skeletal Muscle

Sanes

2003

Journal of Biological Chemistry

377

311

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“…4). Mutations in the laminin ␣2-subunit are a cause of a human congenital muscular dystrophy typically characterized by early onset, severity, and involvement of peripheral nerve and brain (5,6). Some of these dystrophies have mutations within the part of the gene coding for LG modules (7).…”

mentioning

confidence: 99%

Contributions of the LG Modules and Furin Processing to Laminin-2 Functions

Smirnov¹,

McDearmon²,

Li³

et al. 2002

Journal of Biological Chemistry

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The ␣2-laminin subunit contributes to basement membrane functions in muscle, nerve, and other tissues, and mutations in its gene are causes of congenital muscular dystrophy. The ␣2 G-domain modules, mutated in several of these disorders, are thought to mediate different cellular interactions. To analyze these contributions, we expressed recombinant laminin-2 (␣ 2 ␤ 1 ␥ 1 ) with LG4 -5, LG1-3, and LG1-5 modular deletions. Wild-type and LG4 -5 deleted-laminins were isolated from medium intact and cleaved within LG3 by a furin-like convertase. Myoblasts adhered predominantly through LG1-3 while ␣-dystroglycan bound to both LG1-3 and LG4 -5. Recombinant laminin stimulated acetylcholine receptor (AChR) clustering; however, clustering was induced only by the proteolytic processed form, even in the absence of LG4 -5. Furthermore, clustering required ␣ 6 ␤ 1 integrin and ␣-dystroglycan binding activities available on LG1-3, acting in concert with laminin polymerization. The ability of the modified laminins to mediate basement membrane assembly was also evaluated in embryoid bodies where it was found that both LG1-3 and LG4 -5, but not processing, were required. In conclusion, there is a division of labor among LG-modules in which (i) LG4 -5 is required for basement membrane assembly but not for AChR clustering, and (ii) laminin-induced AChR clustering requires furin cleavage of LG3 as well as ␣-dystroglycan and ␣ 6 ␤ 1 integrin binding.The laminin ␣2-chain, a subunit of laminin-2 (␣ 2 ␤ 1 ␥ 1 ) and laminin-4 (␣ 2 ␤ 2 ␥ 1 ), is expressed in the basement membranes of skeletal muscle, peripheral nerve, brain, and placenta (1-3). ␣2-Laminins, similar in molecular morphology and functional attributes to ␣1-laminin, are thought to play important roles in basement membrane assembly and the maintenance of the neuromuscular axis (reviewed in Ref. 4). Mutations in the laminin ␣2-subunit are a cause of a human congenital muscular dystrophy typically characterized by early onset, severity, and involvement of peripheral nerve and brain (5, 6). Some of these dystrophies have mutations within the part of the gene coding for LG modules (7). The dystrophic phenotype in mouse models of the disease is one of defective basement membranes in muscle and nerve, muscle necrosis with poor regeneration, patchy peripheral nerve dysmyelination, and decreased complexity of infoldings and post-junctional membrane lengths of the NMJ motor endplate (6, 8 -12).Studies on cultured myotubes have revealed that ␣1-and ␣2-laminin polymerization and G-domain contributions drive laminin assembly on the cell surface and direct a redistribution of interacting cytoskeletal components (13). The ability of laminin to induce such cytoskeletal reorganizations is thought to reflect an important receptor-dependent property of laminin during early steps in assembly of a basement membrane. It has also been shown that laminins can induce the clustering of the acetylcholine receptor (AChR), 1 a property shared with agrin (14). However, while agrin is secreted by terminal ...

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“…One possibility is that it is the result of altered neuromuscular junction properties in the dy/dy genotype (27). When muscles are stimulated to contract via nerve activation, alterations in neuromuscular transmission are an important potential source of force loss.…”

mentioning

confidence: 99%

Sternohyoid Muscle Fatigue Properties of dy/dy Dystrophic Mice, an Animal Model of Merosin-Deficient Congenital Muscular Dystrophy

Lunteren

Moyer

2003

Pediatr Res

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Humans with merosin-deficient congenital muscular dystrophy have both sucking problems during infancy and sleepdisordered breathing during childhood. We hypothesized that merosin-deficient pharyngeal muscles fatigue faster than normal muscles. This was tested in vitro using sternohyoid muscle from an animal model of this disease, the dy/dy dystrophic mouse. Isometric twitch contraction and half-relaxation times were similar for dy/dy and normal sternohyoid. However, rate of force loss during repetitive 25-Hz train stimulation was markedly diminished in dystrophic compared with normal sternohyoid muscle. Furthermore, force potentiation, which occurred during the early portion of the fatigue-inducing stimulation, had a longer duration in dystrophic compared with normal muscle (approximately 60 versus 20 s). As a result of these two processes, at the end of 2 min of stimulation, force of dystrophic muscle had decreased by 8 Ϯ 5% and that of normal muscle by 69 Ϯ 4% (p Ͻ 0.0001). The potassium-channel blocker, 3,4-diaminopyridine, increased force of dy/dy sternohyoid muscle during twitch and 25-Hz contractions by 148 Ϯ 20% (p Ͻ 0.00001) and 109 Ϯ 18% (p Ͻ 0.00002), respectively. During repetitive 25-Hz stimulation, force of 3,4-diaminopyridine-treated dystrophic muscle remained significantly higher than that of untreated muscle, despite the early force potentiation being eliminated and fatigue being accelerated. Thus, merosin deficiency reduces fatigue and prolongs the duration of force potentiation. The latter alterations may partially preserve the integrity of upper airway muscle function, without which the severity of pharyngeal complications (feeding problems, sleep-related respiratory dysfunction) might be even more pronounced in the human merosin-deficient congenital muscular dystrophies. Classic congenital muscular dystrophy is caused by a deficiency of merosin (laminin ␣2). Infants with this disorder present with severe hypotonia postnatally or in the first month of life (1). Furthermore, they may display feeble sucking, which, if severe, necessitates tube-feeding (1). The weakness improves slowly, allowing children to sit unsupported by 2-3 y of age, but most subjects never gain the ability to walk independently. Up to 30% of subjects die of cardiopulmonary complications in the first year of life, and at later stages nocturnal hypoventilation becomes a serious problem (1, 2). The feeding problems during infancy and the sleep-related respiratory disturbances later during childhood suggest that pharyngeal muscle dysfunction may play an important role in the clinical manifestations of this disease.There are several genetic rodent models of muscular dystrophies, including dy/dy and mdx mice, which have provided important insight into the pathogenesis and manifestations of the muscular dystrophies (3-12). The dy/dy mouse (3-8) lacks merosin, and hence is similar biochemically to the classic congenital muscular dystrophies. This model has weakness of both diaphragm and limb muscles, and hence appears to be a good...

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Electrophysiology of the neuromuscular junction of the laminin-2 (merosin) deficient C57 BL/6J dy2J/dy2J dystrophic mouse

Cited by 12 publications

References 36 publications

The Basement Membrane/Basal Lamina of Skeletal Muscle

The Basement Membrane/Basal Lamina of Skeletal Muscle

Contributions of the LG Modules and Furin Processing to Laminin-2 Functions

Sternohyoid Muscle Fatigue Properties of dy/dy Dystrophic Mice, an Animal Model of Merosin-Deficient Congenital Muscular Dystrophy

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