An insertion within a variably spliced Drosophila tropomyosin gene blocks accumulation of only one encoded isoform

Karlik, C C; Fyrberg, Eric

doi:10.1016/0092-8674(85)90061-3

Cited by 88 publications

(56 citation statements)

References 27 publications

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“…Our model can also explain the sequential activation of different genes, because those activated at low thresholds of mef2 activity would be expressed before genes that are activated at higher thresholds. Last, this temporal regulation by Mef2 may also contribute to the absolute level and relative stoichiometry of expression of sarcomeric proteins, which is known to be important in myogenesis (14)(15)(16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

“…This highlighted that the analysis of how mef2 functions is central to understanding how muscle is made. Important characteristics of the underlying genetic program include the temporal coordination of muscle gene expression (11)(12)(13) and the regulation of levels and relative stoichiometries of gene expression during myogenesis (14)(15)(16)(17)(18)(19). Although these basic features have been known for many years, much remains to be understood about them.…”

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confidence: 99%

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mef2 activity levels differentially affect gene expression during Drosophila muscle development

Elgar

Han

Taylor

2008

Proc. Natl. Acad. Sci. U.S.A.

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Cell differentiation is controlled by key transcription factors, and a major question is how they orchestrate cell-type-specific genetic programs. Muscle differentiation is a well studied paradigm in which the conserved Mef2 transcription factor plays a pivotal role. Recent genomic studies have identified a large number of mef2-regulated target genes with distinct temporal expression profiles during Drosophila myogenesis. However, the question remains as to how a single transcription factor can control such diverse patterns of gene expression. In this study we used a strategy combining genomics and developmental genetics to address this issue in vivo during Drosophila muscle development. We found that groups of mef2-regulated genes respond differently to changes in mef2 activity levels: some require higher levels for their expression than others. Furthermore, this differential requirement correlates with when the gene is first expressed during the muscle differentiation program. Genes that require higher levels are activated later. These results implicate mef2 in the temporal regulation of muscle gene expression, and, consistent with this, we show that changes in mef2 activity levels can alter the start of gene expression in a predictable manner. Together these results indicate that Mef2 is not an all-or-none regulator; rather, its action is more subtle, and levels of its activity are important in the differential expression of muscle genes. This suggests a route by which mef2 can orchestrate the muscle differentiation program and contribute to the stringent regulation of gene expression during myogenesis. muscle differentiation program ͉ transcription factor levels F or several decades it has been appreciated that the controlled regulation of gene expression, including the coordinated activation of batteries of genes, lies behind cell differentiation programs (1-3). It is now clear that a principle tier of control of cell differentiation is through key transcription factors, and an important general question is how these factors coordinate the genetic program of such complex processes. A classic paradigm is muscle, in which the conserved Mef2 transcription factor is a major regulator of gene expression and differentiation (4). Mef2 was first identified in mammalian cell culture (5-7), but because mammals possess four closely related mef2 genes functional analyses during development are complicated. In contrast, Drosophila has a single mef2 gene and was the first organism to be used to show that mef2 is required for muscle development in vivo (8)(9)(10). This highlighted that the analysis of how mef2 functions is central to understanding how muscle is made. Important characteristics of the underlying genetic program include the temporal coordination of muscle gene expression (11-13) and the regulation of levels and relative stoichiometries of gene expression during myogenesis (14-19). Although these basic features have been known for many years, much remains to be understood about them. However, the identificati...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mef2 activity levels differentially affect gene expression during Drosophila muscle development

Elgar

Han

Taylor

2008

Proc. Natl. Acad. Sci. U.S.A.

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“…We next determined whether a mutation in a gene encoding another flight muscle protein, tropomyosin 2 (TM2), present in TM2 3 flies, which creates a flightless phenotype due the absence of 1.7 and 1.9 kb TM2 mRNAs, also produces a cardiomyopathic phenotype (25). Homozygous and heterozygous TM2 3 mutant flies had heart rates that were similar to wild-type flies but possessed enlarged cardiac chambers and significant impairment in systolic function and FS compared to w 1118 (Table 2, which is published as supporting information on the PNAS web site).…”

Section: Adult Drosophila With a Mutation In Tropomyosin 2 Have Dilatedmentioning

confidence: 99%

Drosophila as a model for the identification of genes causing adult human heart disease

Wolf

Amrein

Izatt

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

234

226

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Drosophila melanogaster genetics provides the advantage of molecularly defined P-element insertions and deletions that span the entire genome. Although Drosophila has been extensively used as a model system to study heart development, it has not been used to dissect the genetics of adult human heart disease because of an inability to phenotype the adult fly heart in vivo. Here we report the development of a strategy to measure cardiac function in awake adult Drosophila that opens the field of Drosophila genetics to the study of human dilated cardiomyopathies. Through the application of optical coherence tomography, we accurately distinguish between normal and abnormal cardiac function based on measurements of internal cardiac chamber dimensions in vivo. Normal Drosophila have a fractional shortening of 87 ؎ 4%, whereas cardiomyopathic flies that contain a mutation in troponin I or tropomyosin show severe impairment of systolic function. To determine whether the fly can be used as a model system to recapitulate human dilated cardiomyopathy, we generated transgenic Drosophila with inducible cardiac expression of a mutant of human ␦-sarcoglycan (␦sg S151A ), which has previously been associated with familial dilated cardiomyopathy. Compared to transgenic flies overexpressing wild-type ␦sg, or the standard laboratory strain w 1118 , Drosophila expressing ␦sg S151A developed marked impairment of systolic function and significantly enlarged cardiac chambers. These data illustrate the utility of Drosophila as a model system to study dilated cardiomyopathy and the applicability of the vast genetic resources available in Drosophila to systematically study the genetic mechanisms responsible for human cardiac disease.optical coherence tomography ͉ cardiomyopathy

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“…Generation of protein diversity by alternative RNA processing has been reported for genes encoding other cytoskeletal proteins including myosin light chain (27,67,73,75), troponin T (9,17,63), myosin heavy chain (79), and tropomyosin (3,43,44,53,80). In addition, alternative RNA processing for the generation of contractile protein diversity appears to be a fundamental mechanism conserved throughout evolution since it has been characterized in various species including drosophila, chickens, rats, and humans.…”

Section: Beta-tropomyosin and Fibroblast Tropomyosin 1 Cdnas Wementioning

confidence: 99%

Nonmuscle and muscle tropomyosin isoforms are expressed from a single gene by alternative RNA splicing and polyadenylation.

Helfman¹,

Cheley²,

Kuismanen³

et al. 1986

Mol. Cell. Biol.

175

122

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The molecular basis for the expression of rat embryonic fibroblast tropomyosin 1 and skeletal muscle beta-tropomyosin was determined. cDNA clones encoding these tropomyosin isoforms exhibit complete identity except for two carboxy-proximal regions (amino acids 189 to 213 and 258 to 284) and different 3'-untranslated sequences. The isoform-specific regions delineate the troponin T-binding domains of skeletal muscle tropomyosin. Analysis of genomic clones indicates that there are two separate loci in the rat genome that contain sequences complementary to these mRNAs. One locus is a pseudogene. The other locus contains a single gene made up of 11 exons and spans approximately 10 kilobases. Sequences common to all mRNAs were found in exons 1 through 5 (amino acids 1 to 188) and exons 8 and 9 (amino acids 214 to 257). Exons 6 and 11 are specific for fibroblast mRNA (amino acids 189 to 213 and 258 to 284, respectively), while exons 7 and 10 are specific for skeletal muscle mRNA (amino acids 189 to 213 and 258 to 284, respectively). In addition, exons 10 and 11 each contain the entire 3'-untranslated sequences of the respective mRNAs including the polyadenylation site. Although the gene is also expressed in smooth muscle (stomach, uterus, and vas deferens), only the fibroblast-type splice products can be detected in these tissues. S1 and primer extension analyses indicate that all mRNAs expressed from this gene are transcribed from a single promoter. The promoter was found to contain G-C-rich sequences, a TATA-like sequence TTTTA, no identifiable CCAAT box, and two putative Sp1-binding sites.

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An insertion within a variably spliced Drosophila tropomyosin gene blocks accumulation of only one encoded isoform

Cited by 88 publications

References 27 publications

mef2 activity levels differentially affect gene expression during Drosophila muscle development

mef2 activity levels differentially affect gene expression during Drosophila muscle development

Drosophila as a model for the identification of genes causing adult human heart disease

Nonmuscle and muscle tropomyosin isoforms are expressed from a single gene by alternative RNA splicing and polyadenylation.

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