Rbfox1 Downregulation and Altered Calpain 3 Splicing by FRG1 in a Mouse Model of Facioscapulohumeral Muscular Dystrophy (FSHD)

Pistoni, Mariaelena; Shiue, Lily; Cline, Melissa; Bortolanza, Sergia; Neguembor, Maria Victoria; Xynos, Alexandros; Ares, Manuel; Gabellini, Davide

doi:10.1371/journal.pgen.1003186

Cited by 35 publications

(37 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study indicated that the knockdown of Rbfox1 inhibits muscle differentiation, and that RBFOX1 expression was altered in a mouse model of facioscapulohumeral muscular dystrophy [64]. We identified 34 RBFOX1 targets in muscle-relevant genes ( Fig.…”

Section: Discussionmentioning

confidence: 97%

RBFOX1 Cooperates with MBNL1 to Control Splicing in Muscle, Including Events Altered in Myotonic Dystrophy Type 1

et al. 2014

View full text Add to dashboard Cite

With the goal of identifying splicing alterations in myotonic dystrophy 1 (DM1) tissues that may yield insights into targets or mechanisms, we have surveyed mis-splicing events in three systems using a RT-PCR screening and validation platform. First, a transgenic mouse model expressing CUG-repeats identified splicing alterations shared with other mouse models of DM1. Second, using cell cultures from human embryonic muscle, we noted that DM1-associated splicing alterations were significantly enriched in cytoskeleton (e.g. SORBS1, TACC2, TTN, ACTN1 and DMD) and channel (e.g. KCND3 and TRPM4) genes. Third, of the splicing alterations occurring in adult DM1 tissues, one produced a dominant negative variant of the splicing regulator RBFOX1. Notably, half of the splicing events controlled by MBNL1 were co-regulated by RBFOX1, and several events in this category were mis-spliced in DM1 tissues. Our results suggest that reduced RBFOX1 activity in DM1 tissues may amplify several of the splicing alterations caused by the deficiency in MBNL1.

show abstract

Section: Discussionmentioning

confidence: 97%

RBFOX1 Cooperates with MBNL1 to Control Splicing in Muscle, Including Events Altered in Myotonic Dystrophy Type 1

et al. 2014

View full text Add to dashboard Cite

show abstract

“…In addition, we have previously shown collective alternative splicing of several transcripts in distinct temporal clusters during myoblast differentiation however it is not well understood if these muscle-specific protein isoforms cooperate to control specific aspects of the myogenic program (Bland et al, 2010). Misregulated splicing contributes to disease phenotypes in skeletal muscle in diseases such as myotonic dystrophy (DM) and facioscapulohumeral muscular dystrophy (FSHD) demonstrating an essential role of regulated splicing for proper skeletal muscle function (Gabellini et al, 2006; Pistoni et al, 2013; Singh and Cooper, 2012). …”

Section: Introductionmentioning

confidence: 99%

Rbfox2-Coordinated Alternative Splicing of Mef2d and Rock2 Controls Myoblast Fusion during Myogenesis

et al. 2014

View full text Add to dashboard Cite

Summary Alternative splicing plays important regulatory roles during periods of physiological change. During development a large number of genes coordinately express protein isoform transitions regulated by alternative splicing, however, the mechanisms that coordinate splicing and the functional integration of the resultant tissue-specific protein isoforms are typically unknown. Here we show that the conserved Rbfox2 RNA binding protein regulates 30% of the splicing transitions observed during myogenesis and is required for the specific step of myoblast fusion. Integration of Rbfox2-dependent splicing outcomes from RNA-seq with Rbfox2 iCLIP data identified Mef2d and Rock2 as Rbfox2 splicing targets. Restored activities of Mef2d and Rock2 rescued myoblast fusion in Rbfox2 depleted cultures demonstrating functional cooperation of protein isoforms generated by coordinated alterative splicing. The results demonstrate that coordinated alternative splicing by a single RNA binding protein modulates transcription (Mef2d) and cell signaling (Rock2) programs to drive tissue-specific functions (cell fusion) to promote a developmental transition.

show abstract

“…Third, only selective muscles in FRG1-overexpressing mice are dystrophic and display altered accumulation of myosin heavy chain (MyHC) (8). Finally, it has been shown that in muscles of both FSHD patients and FRG1 transgenic mice, specific pre-mRNAs undergo aberrant alternative splicing (13,34). In particular, our previous studies revealed the aberrant splicing of the fast skeletal troponin T (TNNT3) mRNA in muscles from FRG1 transgenics, as well as in myoblasts of FSHD patients (13).…”

mentioning

confidence: 99%

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Sancisi

Germinario

Esposito

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

cioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is characterized by atrophy and weakness of selective muscle groups. FSHD is considered an autosomal dominant disease with incomplete penetrance and unpredictable variability of clinical expression within families. Mice overexpressing FRG1 (FSHD region gene 1), a candidate gene for this disease, develop a progressive myopathy with features of the human disorder. Here, we show that in FRG1-overexpressing mice, fast muscles, which are the most affected by the dystrophic process, display anomalous fast skeletal troponin T (fTnT) isoform, resulting from the aberrant splicing of the Tnnt3 mRNA that precedes the appearance of dystrophic signs. We determine that muscles of FRG1 mice develop less strength due to impaired contractile properties of fast-twitch fibers associated with an anomalous MyHC-actin ratio and a reduced sensitivity to Ca 2ϩ . We demonstrate that the decrease of Ca 2ϩ sensitivity of fast-twitch fibers depends on the anomalous troponin complex and can be rescued by the substitution with the wild-type proteins. Finally, we find that the presence of aberrant splicing isoforms of TNNT3 characterizes dystrophic muscles in FSHD patients. Collectively, our results suggest that anomalous TNNT3 profile correlates with the muscle impairment in both humans and mice. On the basis of these results, we propose that aberrant fTnT represents a biological marker of muscle phenotype severity and disease progression. muscular dystrophy; aberrant splicing; muscle weakness; FRG1; troponin T FACIOSCAPULOHUMERAL MUSCULAR dystrophy (FSHD), one of the three most common hereditary myopathies, presents progressive atrophy and weakness of a highly specific set of muscle groups (10,11,31). FSHD is characterized by insidious onset and unpredictable progression with high variability of clinical expression, even within the same family (36,37,42). At present, no molecular mechanisms have been implicated in the development of these disease phenotypes, and no biological markers are available to define and monitor disease expression.More than 50 genes have been associated with muscular dystrophies (MD), whose genetic defects have been molecularly defined, and numerous animal models have been developed (30). In many cases, invaluable insights into disease mechanisms, structure and function of gene products, and approaches for therapeutic interventions have benefited from the study of animal models of the different MDs (1). In this context, FSHD is unique because no mutations have been found in any protein-coding gene. Instead, FSHD has been associated with reduction of the number of tandemly repeated 3.3-kb DNA segments (named D4Z4 repeats) located at the subtelomeric region of chromosome 4q (2, 44, 48). The number of D4Z4 repeats varies from 11 to 150 in the general population, whereas less than 11 repeats are present in sporadic and familial FSHD patients (48). The current model to explain FSHD is that the reduction of D4Z4 repeats in FSHD subjects initiates in...

show abstract

Rbfox1 Downregulation and Altered Calpain 3 Splicing by FRG1 in a Mouse Model of Facioscapulohumeral Muscular Dystrophy (FSHD)

Cited by 35 publications

References 85 publications

RBFOX1 Cooperates with MBNL1 to Control Splicing in Muscle, Including Events Altered in Myotonic Dystrophy Type 1

RBFOX1 Cooperates with MBNL1 to Control Splicing in Muscle, Including Events Altered in Myotonic Dystrophy Type 1

Rbfox2-Coordinated Alternative Splicing of Mef2d and Rock2 Controls Myoblast Fusion during Myogenesis

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Contact Info

Product

Resources

About