Beyond mice: Emerging and transdisciplinary models for the study of early-onset myopathies

Jagla, Krzysztof; Kalman, Benoît; Boudou, Thomas; Hénon, Sylvie; Batonnet-Pichon, Sabrina

doi:10.1016/j.semcdb.2016.09.012

Cited by 12 publications

(12 citation statements)

References 119 publications

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“…Structural components of the sarcomere and many aspects of muscle physiology are highly conserved [2,41]. Disease models in the fly have proven highly informative for many genes implicated in human muscle disease, for example CELF1, MBNL1, SMN (Survival motor neuron) and DMD (Dystrophin) [42][43][44]. Flies have a particularly diverse and powerful genetic toolbox that can be employed in vivo, including well-established tools to regulate spatial and temporal expression and to fine-tune levels of both RNAi-mediated knockdown and transgene expression [45][46][47].…”

Section: Drosophila As a Model To Identify And Study Muscle-specific Rbp Functionmentioning

confidence: 99%

“…During metamorphosis, the myoblasts migrate to sites of muscle formation and fuse with founder cells that specify the identity of the forming myotubes [52][53][54]. One exception are the dorsallongitudinal indirect flight muscles (DLMs), which form via myoblast fusion to three larval template muscles that escape histolysis [42,43]. The newly formed myotubes then grow and actively search for their target tendon cells [48,55].…”

Section: Fiber-types and Development Of The Drosophila Adult Musculaturementioning

confidence: 99%

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A Candidate RNAi Screen Reveals Diverse RNA-Binding Protein Phenotypes in Drosophila Flight Muscle

Kao

Nikonova

Chaabane

et al. 2021

Cells

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The proper regulation of RNA processing is critical for muscle development and the fine-tuning of contractile ability among muscle fiber-types. RNA binding proteins (RBPs) regulate the diverse steps in RNA processing, including alternative splicing, which generates fiber-type specific isoforms of structural proteins that confer contractile sarcomeres with distinct biomechanical properties. Alternative splicing is disrupted in muscle diseases such as myotonic dystrophy and dilated cardiomyopathy and is altered after intense exercise as well as with aging. It is therefore important to understand splicing and RBP function, but currently, only a small fraction of the hundreds of annotated RBPs expressed in muscle have been characterized. Here, we demonstrate the utility of Drosophila as a genetic model system to investigate basic developmental mechanisms of RBP function in myogenesis. We find that RBPs exhibit dynamic temporal and fiber-type specific expression patterns in mRNA-Seq data and display muscle-specific phenotypes. We performed knockdown with 105 RNAi hairpins targeting 35 RBPs and report associated lethality, flight, myofiber and sarcomere defects, including flight muscle phenotypes for Doa, Rm62, mub, mbl, sbr, and clu. Knockdown phenotypes of spliceosome components, as highlighted by phenotypes for A-complex components SF1 and Hrb87F (hnRNPA1), revealed level- and temporal-dependent myofibril defects. We further show that splicing mediated by SF1 and Hrb87F is necessary for Z-disc stability and proper myofibril development, and strong knockdown of either gene results in impaired localization of kettin to the Z-disc. Our results expand the number of RBPs with a described phenotype in muscle and underscore the diversity in myofibril and transcriptomic phenotypes associated with splicing defects. Drosophila is thus a powerful model to gain disease-relevant insight into cellular and molecular phenotypes observed when expression levels of splicing factors, spliceosome components and splicing dynamics are altered.

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Section: Drosophila As a Model To Identify And Study Muscle-specific Rbp Functionmentioning

confidence: 99%

Section: Fiber-types and Development Of The Drosophila Adult Musculaturementioning

confidence: 99%

A Candidate RNAi Screen Reveals Diverse RNA-Binding Protein Phenotypes in Drosophila Flight Muscle

Kao

Nikonova

Chaabane

et al. 2021

Cells

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“…The Drosophila genome has a single copy of the Rbfox1 (A2BP1) gene (Kuroyanagi, 2009), making it easier to study Rbfox1 function without the complexities of redundancy. Muscle structure, as well as the mechanism of acto-myosin contractility, is highly conserved (Dasbiswas et al, 2018;Lemke and Schnorrer, 2017), and studies of alternative splicing regulation and fiber-type specific protein isoform function have proven highly informative (Jagla et al, 2017;Jawkar and Nongthomba, 2020;Plantié et al, 2015). Drosophila muscles are of two major types: 1) the fibrillar indirect flight muscles (IFMs) comprised of the dorsal longitudinal (DLMs) and dorso-ventral muscles (DVMs), and 2) the tubular muscles, which constitute the rest of the fly muscles.…”

Section: Introductionmentioning

confidence: 99%

Rbfox1 is required for myofibril development and maintaining fiber-type specific isoform expression inDrosophilamuscles

Nikonova

Kamble

Mukherjee

et al. 2021

Preprint

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Protein isoform transitions confer distinct properties on muscle fibers and are regulated predominantly by differential transcription and alternative splicing. RNA-binding Fox protein 1 (Rbfox1) can affect both transcript levels and splicing, and is known to control skeletal muscle function. However, the detailed mechanisms by which Rbfox1 contributes to normal muscle development and physiology remain obscure. In this study, we report that Rbfox1 contributes to the generation of adult muscle diversity in Drosophila. Rbfox1 is differentially expressed in tubular and fibrillar muscle fiber types. RNAi knockdown of Rbfox1 leads to a loss of flight, climbing and jumping ability, as well as eclosion defects. Myofibers in knockdown muscle are frequently torn, and sarcomeres are hypercontracted. These defects arise from mis-regulation of fiber-type specific gene and splice isoform expression, notably loss of an IFM-specific isoform of Troponin-I that is critical for regulating myosin activity. We find that Rbfox1 influences mRNA transcript levels through 1) direct binding of 3'-UTRs of target transcripts as well as 2) through regulation of myogenic transcription factors, including Mef2, Exd and Salm. Moreover, Rbfox1 modulates splice isoform expression through 1) direct regulation of target splice events in structural genes and 2) regulation of the CELF-family RNA-binding protein Bruno1. Our data indicate that cross-regulatory interactions observed between FOX and CELF family RNA-binding proteins in vertebrates are conserved between their counterparts, Rbfox1 and Bruno1 in flies. Rbfox1 thus affects muscle development by regulation of both fiber-type specific gene and gene isoform expression dynamics of identity genes and structural proteins.

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“…Structural components of the sarcomere and many aspects of muscle physiology are highly conserved [2,41]. Disease models in fly have proven highly informative for many genes implicated in human muscle disease, for example CELF1, MBNL (Muscleblind), SMN (Survival motor neuron) and DMD (Dystrophin) [42][43][44]. Flies have a particularly diverse and powerful genetic toolbox that can be employed in vivo, including well established tools to regulate spatial and temporal expression and to fine-tune levels of both RNAi-mediated knockdown and transgene expression [45][46][47].…”

Section: Drosophila As a Model To Identify And Study Muscle-specific Rbp Functionmentioning

confidence: 99%

A Candidate RNAi Screen Reveals Diverse RNA-Binding Protein Phenotypes in Drosophila Flight Muscle

Kao¹,

Nikonova²,

Chaabane³

et al. 2021

Preprint

View full text Add to dashboard Cite

The proper regulation of RNA processing is critical for muscle development and the fine-tuning of contractile ability between muscle fiber-types. RNA binding proteins (RBPs) regulate the diverse steps in RNA processing including alternative splicing, which generates fiber-type specific isoforms of structural proteins that confer contractile sarcomeres with distinct biomechanical properties. Alternative splicing is disrupted in muscle diseases such as myotonic dystrophy and dilated cardiomyopathy, and is altered after intense exercise as well as with aging. It is therefore important to understand splicing and RBP function, but currently only a small fraction of the hundreds of annotated RBPs expressed in muscle have been characterized. Here we demonstrate the utility of Drosophila as a genetic model system to investigate basic developmental mechanisms of RBP function in myogenesis. We find that RBPs exhibit dynamic temporal and fiber-type specific expression patterns in mRNA-Seq data and display muscle-specific phenotypes. We performed knockdown with 105 RNAi hairpins targeting 35 RBPs and report associated lethality, flight, myofiber and sarcomere defects, including flight muscle phenotypes for Doa, Rm62, mub, mbl, sbr, and clu. Interestingly, knockdown phenotypes of spliceosome components, as highlighted by phenotypes for A-complex components SF1 and Hrb87F (hnRNPA1), revealed level- and temporal-dependent myofibril defects. We further show that splicing mediated by SF1 and Hrb87F is necessary for Z-disc stability and proper myofibril development, and strong knockdown of either gene results in impaired localization of Kettin to the Z-disc. Our results expand the number of RBPs with a described phenotype in muscle and underscore the diversity in myofibril and transcriptomic phenotypes associated with splicing defects. Drosophila is thus a useful model to gain disease-relevant insight into cellular and molecular phenotypes observed when expression levels of splicing factors, spliceosome components and splicing dynamics are altered.

show abstract

Beyond mice: Emerging and transdisciplinary models for the study of early-onset myopathies

Cited by 12 publications

References 119 publications

A Candidate RNAi Screen Reveals Diverse RNA-Binding Protein Phenotypes in Drosophila Flight Muscle

A Candidate RNAi Screen Reveals Diverse RNA-Binding Protein Phenotypes in Drosophila Flight Muscle

Rbfox1 is required for myofibril development and maintaining fiber-type specific isoform expression inDrosophilamuscles

A Candidate RNAi Screen Reveals Diverse RNA-Binding Protein Phenotypes in Drosophila Flight Muscle

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