Small differences in Drosophila tropomyosin expression have significant effects on muscle function.

Tansey, Terese R.; Schultz, J R; Miller, Rehae; Storti, Robert V.

doi:10.1128/mcb.11.12.6337

Cited by 13 publications

(5 citation statements)

References 19 publications

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“…Studies on IFM mutants indicate that structural integrity of IFMs is highly dependent on interactions between thin and thick filaments, as well as the ratio of individual myofibrillar contractile components. Any change in gene dosage and corresponding protein stoichiometry in the thin filaments translates into defects in normal myofibrillar assembly leading to hypercontraction ( Tansey et al 1991 ; Nongthomba et al 2003 , 2007 ). This explains the myofibrillar defects that result from overexpression of TnT ( Marco-Ferreres et al 2005 ), Mhc ( Cripps et al 1994 ), and in most of the heterozygotes carrying mutations in genes encoding structural proteins ( Prado et al 1995 ; Gajewski and Saul 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of miRNA-9 Generates Muscle Hypercontraction Through Translational Repression of Troponin-T inDrosophila melanogasterIndirect Flight Muscles

Katti

Thimmaya

Madan

et al. 2017

G3 Genes|Genomes|Genetics

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MicroRNAs (miRNAs) are small noncoding endogenous RNAs, typically 21–23 nucleotides long, that regulate gene expression, usually post-transcriptionally, by binding to the 3′-UTR of target mRNA, thus blocking translation. The expression of several miRNAs is significantly altered during cardiac hypertrophy, myocardial ischemia, fibrosis, heart failure, and other cardiac myopathies. Recent studies have implicated miRNA-9 (miR-9) in myocardial hypertrophy. However, a detailed mechanism remains obscure. In this study, we have addressed the roles of miR-9 in muscle development and function using a genetically tractable model system, the indirect flight muscles (IFMs) of Drosophila melanogaster. Bioinformatics analysis identified 135 potential miR-9a targets, of which 27 genes were associated with Drosophila muscle development. Troponin-T (TnT) was identified as major structural gene target of miR-9a. We show that flies overexpressing miR-9a in the IFMs have abnormal wing position and are flightless. These flies also exhibit a loss of muscle integrity and sarcomeric organization causing an abnormal muscle condition known as “hypercontraction.” Additionally, miR-9a overexpression resulted in the reduction of TnT protein levels while transcript levels were unaffected. Furthermore, muscle abnormalities associated with miR-9a overexpression were completely rescued by overexpression of TnT transgenes which lacked the miR-9a binding site. These findings indicate that miR-9a interacts with the 3′-UTR of the TnT mRNA and downregulates the TnT protein levels by translational repression. The reduction in TnT levels leads to a cooperative downregulation of other thin filament structural proteins. Our findings have implications for understanding the cellular pathophysiology of cardiomyopathies associated with miR-9 overexpression.

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Section: Discussionmentioning

confidence: 99%

Overexpression of miRNA-9 Generates Muscle Hypercontraction Through Translational Repression of Troponin-T inDrosophila melanogasterIndirect Flight Muscles

Katti

Thimmaya

Madan

et al. 2017

G3 Genes|Genomes|Genetics

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“…This is similar to the phenotype seen in flies haploinsuflicient for another thick filament structural protein, myosin light chain 2 (Warmke et al, 1988(Warmke et al, , 1992. The "cracking" phenotype seen in these mutants depends upon the presence of excess amounts of thin filament proteins, since Beall et al (1989) showed that haploinsufliciency for both myosin and actin results in relatively normal myofibrils: This cracking effect contrasts with the phenotype of flies haploinsuflicient for thin filament proteins, including actin (BeaU et al, 1989) and tropomyosin (Karlik and Fyrberg, 1985;Tansey et al, 1991), where the centers of the myofibrils appear normal and are not cracked, but the peripheries show scattered and misaligned thick filaments. It appears tO be the relative levels of thin filament to thick filament proteins that are important in determining whether the myofibril becomes cracked or simply disrupted at the edge.…”

Section: Discussionmentioning

confidence: 99%

Transformation of Drosophila melanogaster with the wild-type myosin heavy-chain gene: rescue of mutant phenotypes and analysis of defects caused by overexpression.

Cripps

Becker

Mardahl

et al. 1994

The Journal of Cell Biology

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Abstract. We have transformed Drosophila melanogaster with a genomic construct containing the entire wild-type myosin heavy-chain gene, Mhc, together with •9 kb of flanking DNA on each side. Three independent lines stably express myosin heavy-chain protein (MHC) at approximately wild-type levels. The MHC produced is functional since it rescues the mutant phenotypes of a number of different Mhc alleles: the amorphic allele Mhc 1, the indirect flight muscle and jump muscle-specific amorphic allele Mhc ~°, and the hypomorphic allele Mhc 2. We show that the Mhc ~ mutation is due to the insertion of a transposable element in an intron of Mhc.Since a reduction in MHC in the indirect flight muscles alters the myosin/actin protein ratio and results in myofibrillar defects, we determined the effects of an increase in the effective copy number of Mhc. The presence of four copies of Mhc results in overabundance of the protein and a flightless phenotype. Electron microscopy reveals concomitant defects in the indirect flight muscles, with excess thick illaments at the periphery of the myofibrils. Further increases in copy number are lethal. These results demonstrate the usefulness and potential of the transgenic system to study myosin function in Drosophila. They also show that overexpression of wild-type protein in muscle may disrupt the function of not only the indirect flight but also other muscles of the organism.

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“…The deletion of the only known cytoskeletal Tm genes in Drosophila melanogaster (TmI and TmII) leads to altered head morphogenesis, shorter sarcomeres, and disruptions to thick and thin filament packing (23,38,40). However, a rescue experiment with a nonflight muscle Tm isoform showed that the phenotype of the mutant indirect flight muscle Tm could be restored (30).…”

Section: Discussionmentioning

confidence: 99%

Gamma Tropomyosin Gene Products Are Required for Embryonic Development

Hook

Lemckert

Qin

et al. 2004

Molecular and Cellular Biology

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The actin filament system is essential for many cellular functions, including shape, motility, cytokinesis, intracellular trafficking, and tissue organization. Tropomyosins (Tms) are rod-like components of most actin filaments that differentially affect their stability and flexibility. The Tm gene family consists of four genes, ␣Tm, ␤Tm, ␥Tm (Tm5 NM, where "NM" indicates "nonmuscle"), and ␦Tm (Tm4). Multiple isoforms of the Tm family are generated by alternative splicing of three of these genes, and their expression is highly regulated. Extensive spatial and temporal sorting of Tm isoforms into different cellular compartments has been shown to occur in several cell types. We have addressed the function of the low-molecular-weight Tms encoded by the ␥Tm gene by eliminating the corresponding amino-terminal coding sequences from this gene. Heterozygous mice were generated, and subsequent intercrossing of the F 1 pups did not result in any viable homozygous knockouts. Genotype analysis of day 2.5 morulae also failed to detect any homozygous knockouts. We have failed in our attempts to delete the second allele and generate in vitro double-knockout cells, although 51 clones displayed homologous recombination back into the originally targeted locus. We therefore conclude that lowmolecular-weight products from the ␥Tm gene are essential for both embryonic development and cell survival.

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Small differences in Drosophila tropomyosin expression have significant effects on muscle function.

Cited by 13 publications

References 19 publications

Overexpression of miRNA-9 Generates Muscle Hypercontraction Through Translational Repression of Troponin-T inDrosophila melanogasterIndirect Flight Muscles

Overexpression of miRNA-9 Generates Muscle Hypercontraction Through Translational Repression of Troponin-T inDrosophila melanogasterIndirect Flight Muscles

Transformation of Drosophila melanogaster with the wild-type myosin heavy-chain gene: rescue of mutant phenotypes and analysis of defects caused by overexpression.

Gamma Tropomyosin Gene Products Are Required for Embryonic Development

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