Neuregulin/ErbB regulate neuromuscular junction development by phosphorylation of α-dystrobrevin

Schmidt, Nadine; Akaaboune, Mohammed; Gajendran, Nadesan; Valenzuela, Isabel; Wakefield, Sarah; Thurnheer, Raphael; Brenner, Hans Rudolf

doi:10.1083/jcb.201107083

Cited by 84 publications

(79 citation statements)

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“…We also demonstrated that ablation of ERBB2/4 receptors resulted in a lack of phosphorylation of the 75 kDa protein 1 . In addition, the amount of the 75 kDa protein detected on western blots, compared to the 89 kDa protein, was reduced in Erbb2/4 dKO myotubes.…”

Section: Resultsmentioning

confidence: 81%

“…We reported previously that on western blots following immunoprecipitation, there were two isoforms of α-dystrobrevin1 associated with DAPC, a 75 kDa and 89 kDa protein 1 . We also demonstrated that ablation of ERBB2/4 receptors resulted in a lack of phosphorylation of the 75 kDa protein 1 .…”

Section: Resultsmentioning

confidence: 99%

“…Myotubes from 10-cm culture dishes were harvested in 600 μl lysis buffer and protein complexes were immunoprecipitated as described previously 1,13 with modifications. In brief, myotubes harvested in ice-cold lysis buffer (10 mM Na 3 PO 4 , pH 7.8, 150 mM NaCl, 5 mM EDTA, 1 mM EGTA, 1% Triton X-100, protease inhibitor mixture (Roche), and phosphatase inhibitors Pic1 and Pic2 (Sigma-Aldrich)) were homogenized in a Dounce homogenizer and incubated for 3 h at 4°C with protein G-coupled mouse monoclonal syntrophin antibody 1351 (4 μl/80 μl protein G beads, Abcam, catalog number ab11425).…”

Section: Western Blottingmentioning

confidence: 99%

“…In mice, apart from muscular dystrophy, absence of dystrophin causes neuromuscular junction (NMJ) fragmentation 7 similar to the NMJ fragmentation associated with a loss of NRG/ERBB signaling 1 . Lack of dystrophin, besides causing muscular dystrophies, results in cardiomyopathy 8 and is also responsible for several disease states in the brain 6 .…”

Section: Introductionmentioning

confidence: 99%

“…To investigate signaling events in muscle fibers, myotubes formed by fusion of myoblasts, are routinely used as the in vitro equivalent of muscle fibers. We already reported that in myotubes, formed from C2C12 myoblasts, NRG signaling through ERBB2/4 heterodimeric receptors phosphorylated α-dystrobrevin 1 (α-DB1) 1 , one of the components of the dystrophin associated protein complex (DAPC). DAPC links the intracellular actin cytoskeleton to the extracellular matrix and is thereby thought to provide structural stability during muscular activity.…”

Section: Introductionmentioning

confidence: 99%

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The root cause of Duchenne muscular dystrophy is the lack of dystrophin in smooth muscle of blood vessels rather than in skeletal muscle per se

Gajendran

2018

F1000Res

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The dystrophin protein is part of the dystrophin associated Background: protein complex (DAPC) linking the intracellular actin cytoskeleton to the extracellular matrix. Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophy (D/BMD). Neuronal nitric oxide synthase associates with dystrophin in the DAPC to generate the vasodilator nitric oxide (NO). Systemic dystrophin deficiency, such as in D/BMD, results in muscle ischemia, injury and fatigue during exercise as dystrophin is lacking, affecting NO production and hence vasodilation. The role of neuregulin 1 (NRG) signaling through the epidermal growth factor family of receptors ERBB2 and ERBB4 in skeletal muscle has been controversial, but it was shown to phosphorylate α-dystrobrevin 1 (α-DB1), a component of the DAPC. The aim of this investigation was to determine whether NRG signaling had a functional role in muscular dystrophy.Primary myoblasts (muscle cells) were isolated from conditional Methods: knock-out mice containing lox P flanked ERBB2 and ERBB4 receptors, immortalized and exposed to CRE recombinase to obtain double Erbb2/4 knock-out (dKO) myoblasts where NRG signaling would be eliminated. Myotubes, the equivalent of muscle fibers, formed by fusion of the lox P in vitro flanked myoblasts as well as the dKO myoblasts were then Erbb2/4 Erbb2/4 used to identify changes in dystrophin expression.Elimination of NRG signaling resulted in the absence of dystrophin Results: demonstrating that it is essential for dystrophin expression. However, unlike the DMD mouse model mdx, with systemic dystrophin deficiency, lack of dystrophin in skeletal muscles of dKO mice did not result in muscular Erbb2/4 dystrophy. In these mice, ERBB2/4, and thus dystrophin, is expressed in the smooth muscle of blood vessels allowing normal blood flow through vasodilation during exercise.Dystrophin deficiency in smooth muscle of blood vessels, rather Conclusions: than in skeletal muscle, is the main cause of disease progression in DMD.

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Section: Resultsmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Western Blottingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The root cause of Duchenne muscular dystrophy is the lack of dystrophin in smooth muscle of blood vessels rather than in skeletal muscle per se

Gajendran

2018

F1000Res

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Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients

Bruneteau

Bauché

Aguilar

et al. 2015

Ann Clin Transl Neurol

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ObjectiveData from mouse models of amyotrophic lateral sclerosis (ALS) suggest early morphological changes in neuromuscular junctions (NMJs), with loss of nerve–muscle contact. Overexpression of the neurite outgrowth inhibitor Nogo-A in muscle may play a role in this loss of endplate innervation.MethodsWe used confocal and electron microscopy to study the structure of the NMJs in muscle samples collected from nine ALS patients (five early-stage patients and four long-term survivors). We correlated the morphological results with clinical and electrophysiological data, and with Nogo-A muscle expression level.ResultsSurface electromyography assessment of neuromuscular transmission was abnormal in 3/9 ALS patients. The postsynaptic apparatus was morphologically altered for almost all NMJs (n = 430) analyzed using confocal microscopy. 19.7% of the NMJs were completely denervated (fragmented synaptic gutters and absence of nerve terminal profile). The terminal axonal arborization was usually sparsely branched and 56.8% of innervated NMJs showed a typical reinnervation pattern. Terminal Schwann cell (TSC) morphology was altered with extensive cytoplasmic processes. A marked intrusion of TSCs in the synaptic cleft was seen in some cases, strikingly reducing the synaptic surface available for neuromuscular transmission. Finally, high-level expression of Nogo-A in muscle was significantly associated with higher extent of NMJ denervation and negative functional outcome.InterpretationOur results support the hypothesis that morphological alterations of NMJs are present from early-stage disease and may significantly contribute to functional motor impairment in ALS patients. Muscle expression of Nogo-A is associated with NMJ denervation and thus constitutes a therapeutic target to slow disease progression.

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Neuregulin1 fine‐tunes pre‐, post‐, and perisynaptic neuromuscular junction development

Wang

Song

Loeb

2017

Developmental Dynamics

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Background Neuromuscular junction (NMJ) development is a multistep process mediated by coordinated interactions between the nerve terminal, target muscle, and perisynaptic Schwann cell that require constant back-and-forth communication. Retrograde and anterograde growth and differentiation factors have been postulated to participate in this communication. While neuregulin1 (NRG1) has been shown to be potent anterograde signal that activates acetylcholine receptor (AChR) transcription and clustering in vitro, its roles in NMJ development in vivo remain elusive. Results Using the model of chicken embryo, we measured the effects of NRG1 signaling during NMJ development in ovo using quantitative, sequential measures of AChR cluster size and density, pre- and post-synaptic apposition, and the alignment of perisynaptic Schwann cells. Using in ovo electroporation at early stages and a targeted soluble neuregulin antagonist through all developmental stages, we found soluble NRG1 regulates AChR cluster density and size at the earliest stage prior to nerve-AChR cluster contact. Once the nerve contacts with muscle AChRs, NRG1 has pronounced effects on presynaptic specialization and on the alignment of perisynaptic Schwann cells at endplates. Conclusion These findings suggest that, while NRG1 may not be critical for overall development, it appears to be important in fine-tuning pre-, post-, and peri-synaptic development of the NMJ.

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Neuregulin/ErbB regulate neuromuscular junction development by phosphorylation of α-dystrobrevin

Abstract: Neuregulin/ErbB signaling maintains high efficacy of synaptic transmission by stabilizing the postsynaptic apparatus via phosphorylation of α-dystrobrevin1.

Cited by 84 publications

References 50 publications

The root cause of Duchenne muscular dystrophy is the lack of dystrophin in smooth muscle of blood vessels rather than in skeletal muscle per se

The root cause of Duchenne muscular dystrophy is the lack of dystrophin in smooth muscle of blood vessels rather than in skeletal muscle per se

Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients

Neuregulin1 fine‐tunes pre‐, post‐, and perisynaptic neuromuscular junction development

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