Compound loss of muscleblind‐like function in myotonic dystrophy

Lee, Kuang Yung; Li, Moyi; Manchanda, Mini; Batra, Ranjan; Charizanis, Konstantinos; Mohan, Apoorva; Warren, Sanford E.; Chamberlain, Christopher M.; Finn, Dustin; Hong, Hannah; Ashraf, Hassan; Kasahara, Hideko; Ranum, Laura P.W.; Swanson, Maurice S.

doi:10.1002/emmm.201303275

Cited by 157 publications

(246 citation statements)

References 65 publications

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“…Consistent with this model, neonatal Mbnl compound knockout mice show characteristic manifestations of CDM, including frequent perinatal lethality, respiratory distress, reduced newborn body weight and postnatal growth, muscle histopathology, congenital spliceopathy, and gene expression abnormalities. These findings extend beyond our previous observations of muscle wasting in Mbnl muscle-specific double-knockout mice (Lee et al 2013) by demonstrating that muscle development is also severely compromised by compound loss of MBNL1 and MBNL2 activity. A central question is which of the hundreds of detectable RNA misprocessing events in CDM muscle truly contribute to abnormal muscle development.…”

Section: Mbnl Loss-of-function Models For Cdm Pathogenesissupporting

confidence: 84%

“…In agreement, dramatic neonatal lethality was observed in Mbnl1; Mbnl2 conditional double-knockout mice (Lee et al 2013), accompanied by a reduction in total body weight at birth (Fig. 3A,B).…”

Section: Congenital Myopathy and Spliceopathy In Mbnl1; Mbnl2 Double-supporting

confidence: 81%

“…S4A), and, while some events (e.g., Atp2a1 exon 22) were misspliced in Mbnl single knockouts, total spliceopathy was significantly greater in double-knockout muscle (Fig. 4D), which indicated that MBNL paralogs provide functional compensation during myogenesis as reported in C2C12 myoblasts and adult muscle Lee et al 2013). Using mouse embryonic forelimb (EN-CODE) as well as P0 and adult muscle RNA-seq data sets, we generated an in silico model of mouse myogenesis similar to that used for humans (Supplemental Table S1).…”

Section: Congenital Myopathy and Spliceopathy In Mbnl1; Mbnl2 Double-supporting

confidence: 55%

“…), Mbnl2 conditional (Mbnl2 C/C ), compound Mbnl1; Mbnl2, and Mbnl3 isoform (Mbnl3 ΔE2/Y ) knockout mice have been described (Lee et al 2013;Poulos et al 2013). The Mbnl3 conditional whole-locus knockout targeting vector was created using standard recombineering bacterial strains and techniques using protocols 1-4 (http ://web.ncifcrf.gov/research/brb/protocol.aspx) and is described more thoroughly in the Supplemental Material.…”

Section: Mbnl Knockout Modelsmentioning

confidence: 99%

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Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy

et al. 2017

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Myotonic dystrophy type 1 (DM1) is a CTG microsatellite expansion (CTG exp ) disorder caused by expression of CUG exp RNAs. These mutant RNAs alter the activities of RNA processing factors, including MBNL proteins, leading to re-expression of fetal isoforms in adult tissues and DM1 pathology. While this pathogenesis model accounts for adult-onset disease, the molecular basis of congenital DM (CDM) is unknown. Here, we test the hypothesis that disruption of developmentally regulated RNA alternative processing pathways contributes to CDM disease. We identify prominent alternative splicing and polyadenylation abnormalities in infant CDM muscle, and, although most are also misregulated in adult-onset DM1, dysregulation is significantly more severe in CDM. Furthermore, analysis of alternative splicing during human myogenesis reveals that CDM-relevant exons undergo prenatal RNA isoform transitions and are predicted to be disrupted by CUG exp -associated mechanisms in utero. To test this possibility and the contribution of MBNLs to CDM pathogenesis, we generated mouse Mbnl double (Mbnl1; Mbnl2) and triple (Mbnl1; Mbnl2; Mbnl3) muscle-specific knockout models that recapitulate the congenital myopathy, gene expression, and spliceopathy defects characteristic of CDM. This study demonstrates that RNA misprocessing is a major pathogenic factor in CDM and provides novel mouse models to further examine roles for cotranscriptional/post-transcriptional gene regulation during development.

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Section: Mbnl Loss-of-function Models For Cdm Pathogenesissupporting

confidence: 84%

Section: Congenital Myopathy and Spliceopathy In Mbnl1; Mbnl2 Double-supporting

confidence: 81%

Section: Congenital Myopathy and Spliceopathy In Mbnl1; Mbnl2 Double-supporting

confidence: 55%

Section: Mbnl Knockout Modelsmentioning

confidence: 99%

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Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy

et al. 2017

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“…Among them, MBNL1 was a major splicing factor with the highest motif fold enrichment. MBNL1 regulates alternative pre-mRNA splicing in many tissues and cell types, 23,35,[39][40][41][42] but its function in erythroid development was unclear. Our results demonstrated that both Mbnl1 exon 5 inclusion and exclusion isoforms were expressed during terminal erythropoiesis.…”

Section: Discussionmentioning

confidence: 99%

Muscleblind-like 1 (Mbnl1) regulates pre-mRNA alternative splicing during terminal erythropoiesis

Cheng

Shi

Wong

et al. 2014

Blood

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• RNA-seq identified thousands of changes in alternative gene isoform expression changes during erythropoiesis.• MBNL1 regulates alternative splicing in terminal erythropoiesis.The scope and roles of regulated isoform gene expression during erythroid terminal development are poorly understood. We identified hundreds of differentiation-associated isoform changes during terminal erythropoiesis. Sequences surrounding cassette exons of skipped exon events are enriched for motifs bound by the Muscleblind-like (MBNL) family of splicing factors. Knockdown of Mbnl1 in cultured murine fetal liver erythroid progenitors resulted in a strong block in erythroid differentiation and disrupted the developmentally regulated exon skipping of Ndel1 mRNA, which is bound by MBNL1 and critical for erythroid terminal proliferation. These findings reveal an unanticipated scope of the alternative splicing program and the importance of Mbnl1 during erythroid terminal differentiation. (Blood. 2014;124(4):598-610) IntroductionTerminal erythroid differentiation is characterized by 4 to 5 terminal cell divisions accompanied by hemoglobinization, a decrease in cell size, chromatin condensation, and finally expulsion of the nucleus and other organelles. Previous studies have primarily focused on the roles of intracellular signal transduction proteins, transcription factors, and chromatin modifiers in erythropoiesis.1,2The roles of alternative mRNA isoforms and associated regulatory factors in terminal erythroid differentiation are not well established, but an understanding of these could shed light on erythroid developmental biology. [3][4][5] Differential joining of exons in mRNAs via alternative splicing can substantially alter the functions of the corresponding encoded proteins. 6 One classical example of regulated pre-mRNA splicing during erythroid development is the splicing switch of exon 16 in the mRNA encoding the cytoskeletal protein 4.1R (band 4.1). The inclusion of exon 16 in late erythroblasts enhances the affinity of 4.1R protein for spectrin and actin, thereby stabilizing the erythroid membrane under mechanical stress. [7][8][9] It is likely that there are other stage-specific splicing changes crucial for modifying protein functions in erythropoiesis. Previous studies used exon microarrays to identify a handful of novel splicing events and alternative choices of first exons in human erythroid cells, but the scope of analysis was limited by the availability of probes.10 Recent genome-wide analyses of alternative isoform gene expression using RNA-seq have revealed large-scale splicing differences between mammalian tissues, cell, and disease states, [11][12][13] but similar comprehensive studies have not been performed in the context of erythroid differentiation.The Muscleblind-like (MBNL) family of sequence-specific premRNA splicing factors bind RNA through pairs of highly conserved zinc fingers, recognizing YGCY (where Y 5 C or U) and similar motifs.14-18 MBNL proteins are predominantly expressed in skeletal muscle, neuronal tissu...

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Myotonic Dystrophy and Developmental Regulation of RNA Processing

Thomas

Oliveira

Sznajder

et al. 2018

Comprehensive Physiology

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Myotonic dystrophy (DM) is a multisystemic disorder caused by microsatellite expansion mutations in two unrelated genes leading to similar, yet distinct, diseases. DM disease presentation is highly variable and distinguished by differences in age-of-onset and symptom severity. In the most severe form, DM presents with congenital onset and profound developmental defects. At the molecular level, DM pathogenesis is characterized by a toxic RNA gain-of-function mechanism that involves the transcription of noncoding microsatellite expansions. These mutant RNAs disrupt key cellular pathways, including RNA processing, localization, and translation. In DM, these toxic RNA effects are predominantly mediated through the modulation of the muscleblind-like and CUGBP and ETR-3-like factor families of RNA binding proteins (RBPs). Dysfunction of these RBPs results in widespread RNA processing defects culminating in the expression of developmentally inappropriate protein isoforms in adult tissues. The tissue that is the focus of this review, skeletal muscle, is particularly sensitive to mutant RNA-responsive perturbations, as patients display a variety of developmental, structural, and functional defects in muscle. Here, we provide a comprehensive overview of DM1 and DM2 clinical presentation and pathology as well as the underlying cellular and molecular defects associated with DM disease onset and progression. Additionally, fundamental aspects of skeletal muscle development altered in DM are highlighted together with ongoing and potential therapeutic avenues to treat this muscular dystrophy. © 2018 American Physiological Society. Compr Physiol 8:509-553, 2018.

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Compound loss of muscleblind‐like function in myotonic dystrophy

Cited by 157 publications

References 65 publications

Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy

Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy

Muscleblind-like 1 (Mbnl1) regulates pre-mRNA alternative splicing during terminal erythropoiesis

Myotonic Dystrophy and Developmental Regulation of RNA Processing

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