Rbfox1 is required for myofibril development and maintaining fiber type–specific isoform expression in <i>Drosophila</i> muscles

Nikonova, Elena; Mukherjee, Amartya; Kamble, Ketaki; Barz, Christiane; Nongthomba, Upendra; Spletter, Maria L.

doi:10.26508/lsa.202101342

Cited by 4 publications

(33 citation statements)

References 137 publications

(247 reference statements)

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“…Rbfox1 expression strongly increases until 90 h, suggesting a possible role in late myogenesis stage, corresponding to myofibre growth, as well (Spletter et al, 2018). Indeed, the Rbfox1 protein levels follow the same trend (Nikonova et al, 2022).…”

Section: Muscle Developmentmentioning

confidence: 81%

“…Furthermore, Rbfox1 is differentially expressed among muscle fiber types, and, in concert with the RNA-binding protein Bru1, the Drosophila orthologue of CELF1/2, contributes to the generation of adult muscle diversity in Drosophila. Consistent with its second peak in expression during 72-90 h, the knockdown of Rbfox1 causes detached or torn myofibres, a "hypercontraction" muscle phenotype, that leads to behavioral and eclosion defects (Kao et al, 2021;Nikonova et al, 2022;Table 3). It is known that hypercontraction of the IFM is associated with specific mutations in the genes for the major sarcomeric proteins (Nongthomba et al, 2003).…”

Section: Muscle Developmentmentioning

confidence: 90%

“…These findings have been corroborated by the report that knockdown of Rbfox1 , driven by Mef2‐GAL4 , and, after 24 h APF, using Act88F‐GAL4 , a driver specific to the indirect flight muscle (IFM), resulted in severe phenotypes: flightlessness, or even lethality (Nikonova et al, 2019; Table 3). By virtue of its role as a splicing factor and its ability to bind to the 3′‐UTR of its target transcripts, Rbfox1 regulates the expression of myogenic transcription factors Mef2 and Salm (Nikonova et al, 2022). Furthermore, Rbfox1 is differentially expressed among muscle fiber types, and, in concert with the RNA‐binding protein Bru1, the Drosophila orthologue of CELF1/2, contributes to the generation of adult muscle diversity in Drosophila .…”

Section: Research On the Drosophila Rbfox Orthologuementioning

confidence: 99%

“…It is known that hypercontraction of the IFM is associated with specific mutations in the genes for the major sarcomeric proteins (Nongthomba et al, 2003). As was shown by Nikonova et al (2022), the structural defects due to the knockdown of Rbfox1 are to the mis-regulation of fiber type-specific genes, and splice isoform expression, particularly the loss of an IFM-specific isoform of wings up A (wupA), orthologous to human Troponin-I, that is involved in muscle contraction.…”

Section: Muscle Developmentmentioning

confidence: 99%

“…Given that both families of proteins have been implicated in the development and maintenance, Gazzara et al (2017) found physiologically relevant targets, including proteins involved in calcium signaling and members of the Myocyte enhancer factor 2 (MEF2) family of transcription factors. Importantly, suggesting that this antagonism is conserved through evolution, molecular evidence from Drosophila shows that Rbfox1 modulates the expression of myogenic transcription factors Mef2 and Spalt major (Salm), and both modulate expression of and genetically interacts with the CELF orthologue Bruno1 (Bru1) (Nikonova et al, 2022). Together, other splicing factors involved in brain‐ and/or muscle‐specific splicing, such as PTBP1, MBNL1, FRG1, and CELF proteins, may regulate the splicing of RBFOX itself.…”

Section: Regulation Of Rbfox Proteinsmentioning

confidence: 99%

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To RNA‐binding and beyond: Emerging facets of the role of Rbfox proteins in development and disease

Mukherjee,

Nongthomba

2023

WIREs RNA

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The RNA‐binding Fox‐1 homologue (Rbfox) proteins represent an ancient family of splicing factors, conserved through evolution. All members share an RNA recognition motif (RRM), and a particular affinity for the GCAUG signature in target RNA molecules. The role of Rbfox, as a splice factor, deciding the tissue‐specific inclusion/exclusion of an exon, depending on its binding position on the flanking introns, is well known. Rbfox often acts in concert with other splicing factors, and forms splicing regulatory networks. Apart from this canonical role, recent studies show that Rbfox can also function as a transcription co‐factor, and affects mRNA stability and translation. The repertoire of Rbfox targets is vast, including genes involved in the development of tissue lineages, such as neurogenesis, myogenesis, and erythropoeiesis, and molecular processes, including cytoskeletal dynamics, and calcium handling. A second layer of complexity is added by the fact that Rbfox expression itself is regulated by multiple mechanisms, and, in vertebrates, exhibits tissue‐specific expression. The optimum dosage of Rbfox is critical, and its misexpression is etiological to various disease conditions. In this review, we discuss the contextual roles played by Rbfox as a tissue‐specific regulator for the expression of many important genes with diverse functions, through the lens of the emerging data which highlights its involvement in many human diseases. Furthermore, we explore the mechanistic details provided by studies in model organisms, with emphasis on the work with Drosophila.This article is categorized under: RNA Processing > Splicing Mechanisms RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications RNA Turnover and Surveillance > Regulation of RNA Stability RNA Processing > Splicing Regulation/Alternative Splicing

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Section: Muscle Developmentmentioning

confidence: 81%

Section: Muscle Developmentmentioning

confidence: 90%

Section: Research On the Drosophila Rbfox Orthologuementioning

confidence: 99%

Section: Muscle Developmentmentioning

confidence: 99%

Section: Regulation Of Rbfox Proteinsmentioning

confidence: 99%

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To RNA‐binding and beyond: Emerging facets of the role of Rbfox proteins in development and disease

Mukherjee,

Nongthomba

2023

WIREs RNA

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Bruno 1 regulates cytoskeleton dynamics and a temporal splicing transition to promote myofibril assembly, growth and maturation inDrosophilaflight muscle

Nikonova,

Canela Grimau,

Barz

et al. 2023

Preprint

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Muscles undergo developmental transitions in gene expression and alternative splicing that are necessary to refine sarcomere structure and contractility. CUG-BP and ETR-3-like (CELF) family RNA binding proteins are important regulators of RNA processing during myogenesis that are misregulated in diseases such as myotonic dystrophy (DM1). Here we report a conserved function for Bruno 1 (Bru1, Arrest), a CELF1/2 family homolog in Drosophila, during early muscle myogenesis. Loss of Bru1 in flight muscles results in disorganization of the actin cytoskeleton leading to aberrant myofiber compaction and defects in pre-myofibril formation. Temporally-restricted rescue and RNAi knockdown demonstrate that early cytoskeletal defects interfere with subsequent steps in sarcomere growth and maturation. Early defects are distinct from a later requirement for bru1 to regulate sarcomere assembly dynamics during myofiber maturation. We identify an imbalance in growth in sarcomere length and width during later stages of development as the mechanism driving abnormal radial growth, myofibril fusion and the formation of hollow myofibrils in bru1 mutant muscle. Molecularly, we characterize a genome-wide transition from immature to mature sarcomere gene isoform expression in flight muscle development that is blocked in bru1 mutants. We further demonstrate that temporally restricted Bru1 rescue can partially alleviate hypercontraction in late pupal and adult stages, but it cannot restore myofiber function or correct structural deficits. Our results reveal the conserved nature of CELF function in regulating cytoskeletal dynamics in muscle development, and demonstrate that defective RNA processing due to misexpression of CELF proteins causes wide-reaching structural defects and progressive malfunction of affected muscles that cannot be rescued by late-stage gene replacement.

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Rbfox1 andmir-33regulate pleiotropic roles of JAK/STAT signalling during adult myogenesis inDrosophila melanogaster

Mukherjee,

Nongthomba

2024

Preprint

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The JAK/STAT pathway is a conserved metazoan signal transduction system with roles in regulating growth, stem cells, and immune responses. Although its components are ubiquitously expressed during development, JAK/STAT signalling exerts cell-specific effects through mechanisms largely unknown. Here, we demonstrate that cell-specific effects of JAK/STAT signalling could be realised through post-transcriptional regulation. We show that JAK/STAT signalling in early adult myogenesis is critical for the patterning of the dorsal longitudinal muscles in Drosophila melanogaster. RNA-binding Fox protein 1 (Rbfox1) and the microRNA mir-33 regulate the transcript stability of Signal-transducer and activator of transcription protein at 92E (Stat92E), which encodes the sole Drosophila STAT orthologue. Moreover, Rbfox1 also controls the alternative splicing of Stat92E and its key downstream effector, Zn finger homeodomain 1 (zfh1). The coupling of Rbfox1 with Stat92E function, during early adult myogenesis, not only allows maintenance of stemness, but also mediates filamentous actin dynamics, and prevents apoptosis in myoblasts via some other Stat92E target genes. Given that the functions of the JAK/STAT pathway in cell proliferation and survival are conserved between Drosophila and vertebrates, our report presents a novel example for the context-dependant regulation of the developmental role of an important signalling pathway.

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Rbfox1 is required for myofibril development and maintaining fiber type–specific isoform expression in Drosophila muscles

Cited by 4 publications

References 137 publications

To RNA‐binding and beyond: Emerging facets of the role of Rbfox proteins in development and disease

To RNA‐binding and beyond: Emerging facets of the role of Rbfox proteins in development and disease

Bruno 1 regulates cytoskeleton dynamics and a temporal splicing transition to promote myofibril assembly, growth and maturation inDrosophilaflight muscle

Rbfox1 andmir-33regulate pleiotropic roles of JAK/STAT signalling during adult myogenesis inDrosophila melanogaster

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