Zebrafish models flex their muscles to shed light on muscular dystrophies

Berger, Joachim; Currie, Peter D.

doi:10.1242/dmm.010082

Cited by 71 publications

(60 citation statements)

References 68 publications

(89 reference statements)

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“…The use of the zebrafish as a model organism provides valuable opportunities for interrogating the functions of genes involved in muscle fiber attachment (Berger and Currie, 2012;Gibbs et al, 2013). Here, we show that the zebrafish gene transmembrane protein 2 (tmem2) plays an important and previously unappreciated role in regulating cell-matrix interactions at the MTJ.…”

Section: Introductionmentioning

confidence: 99%

Tmem2 regulates cell-matrix interactions that are essential for muscle fiber attachment

Ryckebüsch¹,

Hernandez²,

Wang³

et al. 2016

Journal of Cell Science

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Skeletal muscle morphogenesis depends upon interactions between developing muscle fibers and the extracellular matrix (ECM) that anchors fibers to the myotendinous junction (MTJ). The pathways that organize the ECM and regulate its engagement by cell-matrix adhesion complexes (CMACs) are therefore essential for muscle integrity. Here, we demonstrate the impact of transmembrane protein 2 (tmem2) on cell-matrix interactions during muscle morphogenesis in zebrafish. Maternal-zygotic tmem2 mutants (MZtmem2) exhibit muscle fiber detachment, in association with impaired laminin organization and ineffective fibronectin degradation at the MTJ. Similarly, disorganized laminin and fibronectin surround MZtmem2 cardiomyocytes, which could account for their hindered movement during cardiac morphogenesis. In addition to ECM defects, MZtmem2 mutants display hypoglycosylation of α-dystroglycan within the CMAC, which could contribute to the observed fiber detachment. Expression of the Tmem2 ectodomain can rescue aspects of the MZtmem2 phenotype, consistent with a possible extracellular function of Tmem2. Together, our results suggest that Tmem2 regulates cell-matrix interactions by affecting both ECM organization and CMAC activity. These findings evoke possible connections between the functions of Tmem2 and the etiologies of congenital muscular dystrophies, particularly dystroglycanopathies.

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Section: Introductionmentioning

confidence: 99%

Tmem2 regulates cell-matrix interactions that are essential for muscle fiber attachment

Ryckebüsch¹,

Hernandez²,

Wang³

et al. 2016

Journal of Cell Science

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“…Rodent screening models also have many shortcomings, as they are time consuming, strenuous and costly. Due to unique advantages in biology, genomics, and genetics, as well as high conservativity in the disease signal transduction pathway, drug screens in zebrafish embryos and larvae hold considerable promise in filling the gap between cell and rodent models [16, 34, 43]. In the present study, we show a simple, quick and practical method for screening and evaluating antiendotoxic agents using zebrafish embryos.…”

Section: Discussionmentioning

confidence: 83%

Protective Effect of Phillyrin on Lethal LPS-Induced Neutrophil Inflammation in Zebrafish

Lei

Zhou

Huang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Forsythia suspensa Vahl. (Oleaceae) fruits are widely used in traditional Chinese medicine to treat pneumonia, typhoid, dysentery, ulcers and oedema. Antibacterial and anti-inflammatory activities have been reported for phillyrin (PHN), the main ingredient in Forsythia suspensa Vahl fruits, in vitro. However, the underlying mechanisms in vivo remain poorly defined. In this study, we discovered that PHN exerted potent anti-inflammatory effects in lethal LPS-induced neutrophil inflammation by suppressing the MyD88-dependent signalling pathway in zebrafish. Methods: LPS-yolk microinjection was used to induce a lethal LPS-infected zebrafish model. The effect of PHN on the survival of zebrafish challenged with lethal LPS was evaluated using survival analysis. The effect of PHN on neutrophil inflammation grading in vivo was assessed by tracking neutrophils with a transgenic line. The effects of PHN on neutrophil production and migration were analysed by SB⁺ cell counts during consecutive hours after modelling. Additionally, key cytokines and members of the MyD88 signalling pathway that are involved in inflammatory response were detected using quantitative RT-PCR. To assess gene expression changes during consecutive hours after modelling, the IL-1β, IL-6, TNF-α, MyD88, TRIF, ERK1/2, JNK, IκBa and NF-κB expression levels were measured. Results: PHN could protect zebrafish against a lethal LPS challenge in a dose-dependent manner, as indicated by decreased neutrophil infltration, reduced tissue necrosis and increased survival rates. Up-regulated IL-1β, IL-6 and TNF-α expression also showed the same tendencies of depression by PHN. Critically, PHN significantly inhibited the LPS-induced activation of MyD88, IκBa, and NF-κB but did not affect the expression of ERK1/2 MAPKs or JNK MAPKs in LPS-stimulated zebrafish. Additionally, PHN regulated the MyD88/IκBα/NF-κB signalling pathway by controlling IκBα, IL-1β, IL-6, and TNF-α expression. Conclusion: This study provides a rationale for the clinical application of PHN as an anti-inflammatory agent.

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“…Zebrafish ( Danio rerio ) have rapid external development of translucent embryos that are easy to manipulate, which makes them attractive to researchers (Berger and Currie, 2012). They have abundant skeletal muscle and express orthologues of most DAPC proteins, that have similar membrane localization as in the human (Collins and Morgan, 2003).…”

Section: Experimental Models Of Dmdmentioning

confidence: 99%

“…They have abundant skeletal muscle and express orthologues of most DAPC proteins, that have similar membrane localization as in the human (Collins and Morgan, 2003). Dystrophin-deficient zebrafish have been identified ( dmd ta222a ) and created by morpholino knockdown, and their histologic features include extensive muscle degeneration/necrosis, fibrosis, inflammation, activation of muscle stem cells and variation in fiber diameter (Berger et al , 2010, Berger and Currie, 2012). Similar to humans, zebrafish express dystrophin in embryos first at a junctional myotendinous location in the embryo and later at non-junctional sarcolemma (Berger et al , 2010).…”

Section: Experimental Models Of Dmdmentioning

confidence: 99%

Duchenne and Becker Muscular Dystrophies: A Review of Animal Models, Clinical End Points, and Biomarker Quantification

Wilson¹,

Faelan²,

Patterson-Kane³

et al. 2017

Toxicol Pathol

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Duchenne and Becker muscular dystrophies (DMD/BMD) are neuromuscular disorders that primarily affect boys due to an X-linked mutation in the DMD gene, resulting in reduced to near absence of dystrophin or expression of truncated forms of dystrophin. Some newer therapeutic interventions aim to increase sarcolemmal dystrophin expression, and accurate dystrophin quantification is critical for demonstrating pharmacodynamic relationships in preclinical studies and clinical trials. Current challenges with measuring dystrophin include the variation in protein expression within individual muscle fibers and across whole muscle samples, the presence of pre-existing dystrophin-positive revertant fibers, and trace amounts of residual dystrophin. Immunofluorescence quantification of dystrophin can overcome many of these challenges, but manual quantification of protein expression may be complicated by variations in the collection of images, reproducible scoring of fluorescent intensity, and bias introduced by manual scoring of typically only a few high-power fields. This review highlights the pathology of DMD/BMD, discusses animal models of DMD/BMD, and describes dystrophin biomarker quantitation in DMD/BMD, with several image analysis approaches, including a new automated method, that evaluates protein expression of individual muscle fibers.

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Zebrafish models flex their muscles to shed light on muscular dystrophies

Cited by 71 publications

References 68 publications

Tmem2 regulates cell-matrix interactions that are essential for muscle fiber attachment

Tmem2 regulates cell-matrix interactions that are essential for muscle fiber attachment

Protective Effect of Phillyrin on Lethal LPS-Induced Neutrophil Inflammation in Zebrafish

Duchenne and Becker Muscular Dystrophies: A Review of Animal Models, Clinical End Points, and Biomarker Quantification

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